Abeer Yasin

Methods of assessing renal function

Accurate assessment of renal function is critical for appropriate drug dosing of renally excreted compounds. Glomerular filtration rate (GFR) is considered the best marker of kidney function. Inulin clearance forms the gold standard for measuring GFR, both in adults and in children. The method is invasive, cumbersome, and smaller children require urinary catheterization for accurate timed urine collections. Nuclear medicine methods replaced inulin clearance in the 1970s after 51Cr EDTA clearance was introduced. Inulin has no plasma protein binding, whereas all commonly used radioisotopes have a small amount of plasma protein binding that leads to lower values. Only iohexol does not have significant plasma protein binding. The underestimation due to plasma protein binding is partially offset by overestimation due to the use of non-compartmental pharmacokinetic modeling of the plasma disappearance of the radioisotope. The problem could be overcome with a urinary nuclear medicine clearance method, but these have not been validated in children. Endogenous markers of GFR include serum creatinine and low molecular weight proteins such as cystatin C and beta-trace protein. Of these, estimation of GFR using cystatin C appears to be the most promising, although its accuracy in pregnancy and in the neonatal period may be limited.

Diagnostic Accuracy of Cystatin C–Based eGFR Equations at Different GFR Levels in Children

BACKGROUND AND OBJECTIVES The diagnostic accuracy of cystatin C estimated GFR (eGFR) by various cystatin C equations have varied in different studies. We hypothesized that the GFR level of enrolled patients affects the diagnostic accuracy of a cystatin C equation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We analyzed 240 consecutively enrolled children at a single Canadian center in a prospective and cross-sectional study. Cystatin C was analyzed with nephelometry, and cystatin C eGFR was estimated by the equations validated in children. GFR was measured by technetium-99m-diethylene-triamine penta-acetic acid (⁹⁹m)Tc DTPA). RESULTS We compared various cystatin C equations across GFR strata < 60, < 90, ≥ 135, and ≥ 150 ml/min per 1.73 m² for an accurate prediction and appropriate classification of the measured GFR. The CKiD, Zappitelli-CysEq, and Zappitelli-CysCrEq equations had a higher accuracy, estimated by eGFR values within 10% and 30% of the respective (99m)Tc DTPA, in the GFR categories < 60 and < 90 ml/min per 1.73 m², whereas the Bökenkamp, Bouvet, and Filler equations had a greater accuracy in the GFR categories ≥ 135 and ≥ 150 ml/min per 1.73 m². The Bouvet, CKiD, Filler, Zappitelli-CysEq, and Zappitelli-CysCrEq equations had a greater sensitivity to classify GFR < 60 and < 90 ml/min per 1.73 m², whereas the Bökenkamp equation had a higher sensitivity for GFR ≥ 135 and ≥ 150 ml/min per 1.73 m². CONCLUSIONS The diagnostic accuracy of various cystatin C equations varies with GFR. This issue needs consideration while applying these equations in clinical practice and for further research on eGFR equations.

Big Mother or Small Baby: Which Predicts Hypertension?

According to the Barker hypothesis, intrauterine growth restriction and premature delivery adversely affect cardiovascular health in adult life. The association of childhood hypertension as a cardiovascular risk factor and birth weight has been understudied. In a prospective cohort study, the authors evaluated the effect of birth weight, gestational age, maternal prepregnancy body mass index (BMI), and child BMI z score at the time of enrollment on the systolic and diastolic blood pressure (BP) z score in 3024 (1373 women) consecutive outpatient clinic patients aged 2.05 to 18.58 years. The latest National Health and Nutrition Examination Survey (NHANES III) was used to calculate the age‐dependent z scores. The median z scores of BMI (+0.48, range −6.96–6.64), systolic BP (+0.41, range −4.50–6.73), and diastolic BP (+0.34, range −3.15–+6.73) were all significantly greater than the NHANES III reference population. Systolic BP z score did not correlate with birth weight or gestational age, but did correlate with maternal prepregnancy BMI (r=.090, P<.0001) and BMI z score (r=.209, P<.0001). Diastolic BP z score positively correlated with birth weight (0.037, P=.044), gestational age (r=.052, P=.005), BMI z score(r=.106, P<.0001), and maternal prepregnancy BMI (r=.062, P=.0007). In contrast to what would be expected from the Barker hypothesis, the authors found no negative correlation between BP z score and birth weight or gestational age. This study suggests that a high BMI, a big mom, and a high birth weight are more important risk factors for hypertension during childhood than low birth weight or gestational age. J Clin Hypertens (Greenwich). 2011;13:35–41. ©2010 Wiley Periodicals, Inc.

Body mass does not have a clinically relevant effect on cystatin C eGFR in children

BACKGROUND Unlike creatinine, Cystatin C (CysC) is believed to be independent of body composition in both adults and children. Recent findings in adults, suggesting an improved performance of CysC-based estimated glomerular filtration rate (CysC eGFR) by accounting for body mass, necessitated a careful re-evaluation of this issue in children. METHODS We studied 240 children (median age 11.7 years, range 2-17.9 years, 107 girls), with various kidney diseases, for any change in the relationship between (99)Tc DTPA GFR and CysC eGFR after accounting for body mass. For body mass assessment, body mass index (BMI) z-score was calculated using height-adjusted age, to account for growth retardation secondary to chronic kidney disease. RESULTS CysC eGFR did not have a significant correlation with BMI z-score (correlation coefficient = 0.06; P = 0.34). Accounting for BMI z-score did not add to the 65% variance in nuclear GFR explained by CysC eGFR. Moreover, it did not change the regression coefficient of 0.85 between CysC eGFR and nuclear GFR either. On Bland & Altman analysis, the bias of 0.05 and standard deviation of 20.39 also did not improve after accounting for BMI z-score in the revised CysC eGFR formula. CONCLUSIONS In children, body mass exerts a minimal effect on the performance of CysC eGFR estimation.

Preliminary reference intervals for cystatin C and beta-trace protein in preterm and term neonates ☆

OBJECTIVE To determine the reference intervals for serum cystatin C (CysC) and beta-trace protein (BTP) as markers of renal function in preterm and term neonates. DESIGN AND METHODS Blood samples of 128 neonates (34% female) admitted to the NICU were analyzed to determine the levels of serum creatinine (enzymatically), CysC and BTP (nephelometric, Siemens Health Care). RESULTS The reference intervals, categorized by age, were reported for the 128 neonates. Median (lower/upper limit) BTP were 1.85 (0.57/3.16) and 1.27 (0.51/2.07) mg/L on days 1 and 3. In keeping with maturation of renal function after birth, CysC and BTP fell from days one to day three after birth, whereas creatinine did not. CONCLUSION Our data provides reference intervals for the levels of creatinine, CysC, and BTP in neonates on days 1 and 3 after birth and demonstrates that CysC and BTP reflect neonatal renal function, whereas creatinine reflects maternal renal function.

Hyperfiltration Affects Accuracy of Creatinine eGFR Measurement

BACKGROUND AND OBJECTIVES Surrogate markers such as creatinine, cystatin C (CysC), and beta trace protein (BTP) have been used to estimate GFR (eGFR). The accuracy of eGFR may be altered with hyperfiltration and differences in filtration fraction (FF). It is hypothesized that the accuracy of creatinine for eGFR may be affected by hyperfiltration and different effective renal plasma flow (ERPF). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A total of 127 pediatric patients with various renal diseases underwent simultaneous measurements of GFR using 51Cr-EDTA renal scan and ERPF (131I-hippurate clearance) to calculate the FF (FF=GFR/ERPF). The eGFRs were calculated using the commonly used Schwartz (creatinine), Filler (CysC), and Benlamri (BTP) formulas. Agreement of the eGFRs with the measured isotope GFRs was assessed by Bland-Altman plots. Correlation analysis was performed using nonparametric tests to compare FF with eGFR-GFR. RESULTS The 127 children at a median age (with 25th percentile, 75th percentile) of 11.9 (8.5, 14.9) years had a mean 51Cr EDTA-GFR of 100.6±32.1 ml/min per 1.73 m2 and a median 131I-hippurate clearance (ERPF) of 588 (398,739) ml/min per 1.73 m2. Mean FF was 17.7±4.5% with no correlation between the FF and the error (eGFR-GFR) for CysC and BTP eGFR, whereas there was a significant negative correlation between the error for Schwartz eGFR and FF. CONCLUSIONS There is a significant negative correlation between the error for the Schwartz eGFR and the FF. CysC and BTP are not affected by differences in FF.

Cystatin C Levels in Functionally Anephric Patients Undergoing Dialysis: The Effect of Different Methods and Intensities

BACKGROUND AND OBJECTIVES Cystatin C, a low molecular weight protein, is produced by nucleated cells, filtered by glomeruli, and degraded by tubules at a constant rate. Its serum concentration has been proposed as a marker of GFR. Its size should make it dialyzable. It is hypothesized that serum cystatin C levels are influenced by the method and intensity of dialysis received. DESIGN This is a cross-sectional pilot study of cystatin C in functionally anephric dialysis patients. It was measured predialysis in 14 patients on conventional (3 to 5 h, 3 x wk) hemodialysis; eight on nocturnal hemodialysis (three to seven nights, 6 to 8 h); three on daily hemodialysis (6 d, 1(1/2) to 2(1/2) h); and 10 on automated peritoneal dialysis. All had urea kinetic studies and values for single pool Kt/V (Sp Kt/V), standard weekly Kt/V (Std Kt/V), and protein equivalent of nitrogen appearance (nPNA; g/kg/d). C reactive protein (CRP; mg/L) and thyroid stimulating hormone (TSH; mIU/L) were measured as factors known to influence cystatin C. RESULTS There was no correlation between cystatin C and Sp Kt/V, but there was a significant inverse linear correlation with Std Kt/V and there were significant differences between treatment modalities in cystatin C levels and in Std Kt/V. The estimation of cystatin C was reliable and stable over 3 to 6 wk and its levels uninfluenced by nPNA, CRP, or TSH. CONCLUSION Serum cystatin C levels are influenced by the method and intensity of dialysis and may have a role in treatment adequacy monitoring.

Ontario children have outgrown the Broselow tape

OBJECTIVE The Broselow Pediatric Emergency Tape (Armstrong Medical Industries, Inc., Lincolnshire, IL) (BT) is a well-established length-based tool for estimation of body weight for children during resuscitation. In view of pandemic childhood obesity, the BT may no longer accurately estimate weight. We therefore studied the BT in children from Ontario in a large recent patient cohort. METHODS Actual height and weight were obtained from an urban and a rural setting. Children were prospectively recruited between April 2007 and July 2008 from the emergency department and outpatient clinics at the London Health Science Centre. Rural children from junior kindergarten to grade 4 were also recruited in the spring of 2008 from the Avon Maitland District School Board. Data for preschool children were obtained from three daycare centres and the electronic medical record from the Maitland Valley Medical Centre. The predicted weight from the BT was compared to the actual weight using Spearman rank correlation; agreement and percent error (PE) were also calculated. RESULTS A total of 6,361 children (46.2% female) were included in the study. The median age was 3.9 years (interquartile range [IQR] 1.56-7.67 years), weight was 17.2 kg (IQR 11.6-25.4 kg), and height was 103.5 cm (IQR 82-124.4 cm). Although the BT weight estimate correlated with the actual weight (r  =  0.95577, p < 0.0001), the BT underestimated the actual weight by 1.62 kg (7.1% ± 16.9% SD, 95% CI -26.0-40.2). The BT had an ≥ 10% PE 43.7% of the time. CONCLUSIONS Although the BT remains an effective method for estimating pediatric weight, it was not accurate and tended to underestimate the weight of Ontario children. Until more accurate measurement tools for emergency departments are developed, physicians should be aware of this discrepancy.

The usefulness of cystatin C and related formulae in pediatrics.

Abstract Serum creatinine does not share the properties of an ideal marker of glomerular filtration rate (GFR) like inulin, but continues to be the most widely used endogenous marker of GFR. In the search of a better biomarker of GFR, the small molecular weight protein cystatin C has been introduced with features more similar to that of inulin, such as constant production and no non-renal elimination. However, it has not enjoyed widespread use despite its significantly improved diagnostic performance in the detection of impaired GFR and its independence of body composition. A variety of formulae based on either cystatin C or creatinine or both have been developed to estimate GFR. We summarize the currently used methods of GFR measurement, their limitations and analytical errors. The review also summarizes the history, features and the feasibility of cystatin C measurements as well as the most widely used formulae for the estimation of GFR in children. The diagnostic performance of the cystatin C derived eGFR formulae at various levels of GFR is also discussed. An eGFR formula derived from pooled studies analyzing both creatinine and cystatin C, and using a biology-based mathematical approach may be advantageous.

Cystatin C Reduction Ratio Depends on Normalized Blood Liters Processed and Fluid Removal during Hemodialysis

BACKGROUND AND OBJECTIVES A negative correlation between the weekly standard Kt/V (urea) and serum cystatin C level (CysC) in functionally anephric dialysis patients has been previously demonstrated. Our objective was to measure the per dialysis CysC reduction ratio (CCRR) and to compare it with other indices of dialytic functions. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS In a pilot cross-sectional study of 15 functionally anephric patients on conventional high-flux high-efficiency hemodialysis three times per week, CysC levels were drawn pre-, mid-, and postdialysis over 1 week. CCRR was compared with single-pool Kt/V (Sp Kt/V) using urea kinetic modeling, urea reduction ratio (URR), creatinine reduction ratio (CRR), normalized liters processed (LP/kg), and ultrafiltration volume (UF). Normally distributed data (Shapiro-Wilks test) were described as mean±SD, otherwise as median and interquartile range. RESULTS The mean pre- and post-CysC levels were 6.0±1.0 and 4.7±1.1 mg/L. The Sp Kt/V and Std Kt/V were 1.5±0.2 and 2.6. The URR, CRR, and CCRR were 70.2%±9.0%, 64.5%±8.2%, and 26.1%±11.8%, respectively. There was no correlation between the CCRR, and the Sp Kt/V, URR, and CRR, whereas CCRR correlated with LP/kg and UF. Multiple regression analysis with these two parameters provided a model that explained 81% of the variance. CONCLUSIONS Our data suggest that normalized liters processed and ultrafiltration volume explain most of the variance of CCRR. Therefore, CCRR may be an excellent method to monitor dialysis efficiency of low molecular weight proteins.