Detecting reduced renal function in children: comparison of GFR-models and serum markers.

BACKGROUND: The aim of this study was to compare the ability of renal indicators [serum creatinine (SCr), cystatin C (SCysC)] and glomerular filtration rate (GFR)-models to discriminate normal and reduced renal function. As a single cut-off level will always lead to false classifications, we propose using two cut-off levels, dividing renal function into normal or reduced, with an intermediate "gray zone" of indeterminable results. METHODS: Glomerular filtration rate was measured by plasma clearance of (51)Cr-EDTA (13.7-147.4 mL/min/1.73 m(2)) in 119 children (age range 2.3-14.9 years). Reduced renal function was defined as a GFR of <82 mL/min/1.73 m(2). SCr, SCysC, age-normalized creatinine (SCr-ratio), and eight published GFR-models were compared for their ability to correctly classify renal function as normal or reduced. Cut-off levels were determined so as to give 99 % certainty outside the gray zone. RESULTS: The multivariable GFR-models by Schwartz et al. (J Am Soc Nephrol 2009; 20:629-637) and Zappitelli et al. (Am J Kidney Dis 2006; 48:221-230) and two models by Andersen et al. [Am J Kidney Dis 2012; 59(1):50-57: body cell mass (BCM)-model and Weight-model] performed significantly better than all other variables (P < 0.01), with the BCM-model performing the best (P < 0.05). The SCr-based Schwartz formula and SCr-ratio both performed better than SCr and SCysC. CONCLUSIONS: Among the 119 children enrolled in this study and the renal indicators tested, the BCM-model had the best diagnostic performance in terms of screening for normal or reduced renal function, and the SCr-ratio was a superior diagnostic tool to both SCr and SCysC.

Simplified methods for assessment of renal function as the ratio of glomerular filtration rate to extracellular fluid volume.

BACKGROUND: Instead of scaling glomerular filtration rate (GFR) to a body surface area of 1.73 m(2), it has been suggested to scale GFR to extracellular fluid volume (ECV). The ratio GFR/ECV has physiological meaning in that it indicates how often 'that which is to be regulated' (i.e. ECV) comes into contact with the 'regulator' (i.e. the kidneys). AIM: The aim of the present study was as follows: to analyse two published calculation methods for determining ECV and GFR/ECV; to develop a new simple and accurate formula for determining ECV; and to compare and evaluate these methods. MATERIALS AND METHODS: GFR was determined as (51)Cr-EDTA clearance. The study comprised 128 individuals (35 women, 66 men and 27 children) with a full (51)Cr-EDTA plasma concentration curve, determined from injection until 4-5 h p.i. Reference values for GFR and ECV were calculated from the full curve. One-pool approximations C/(1) and V(1) were calculated using only the final-slope curve. Four calculation methods were compared: simple one-pool values; GFR/ECV according to Peters and colleagues; ECV according to Brøchner-Mortensen (BM); and ECV according to a new method (JBM): y=2x-1, where x=Cl(1)/Cl and y=V(1)/ECV. RESULTS: The new JBM method is accurate and can be explained theoretically. BM has a slight bias for high renal function. The Peters method had bias in our data. GFR/ECV had better precision than ECV alone, especially for BM and JBM, which were within -4% to +7% of the reference values (95% limits of agreement in adults). CONCLUSION: GFR/ECV can be precisely determined, especially with the BM and JBM methods. Expressing GFR/ECV in unit %/h gives a simple interpretation. Normal ranges for GFR/ECV need to be established.

GFR prediction from cystatin C and creatinine in children: effect of including body cell mass.

BACKGROUND: Aiming to develop a more accurate cystatin C-based model for estimation of glomerular filtration rate (GFR) in children, we hypothesized that inclusion of body cell mass (BCM) would increase the accuracy of the GFR estimate in comparison to a well-established GFR reference method. STUDY DESIGN: Diagnostic test accuracy study. SETTINGS & PARTICIPANTS: 119 children (mean age, 8.8; range, 2.3-14.9 years) referred for GFR measurement by chromium 51 ethylenediaminetetraacetic acid ((51)Cr-EDTA) clearance (mean GFR, 98; range, 13.7-147.4 mL/min/1.73 m(2)). INDEX TEST: GFR estimations by the 2 prediction models resulting from theoretical considerations corroborated by forward stepwise variable selection: GFR (mL/min) = 0.542 × (BCM/SCysC)(0.40) × (height × BSA/SCr)(0.65) and GFR (mL/min) = 0.426 × (weight/SCysC)(0.39) × (height × BSA/SCr)(0.64), where SCysC is serum cystatin C level, BSA is body surface area, and SCr is serum creatinine level. The accuracy and precision of these models were compared with 7 previously published prediction models using random subsampling cross-validation. Local constants and coefficients were calculated for all models. Root mean square error, R(2), and percentage of predictions within ±10% and ±30% of the reference GFR were calculated for all models. Based on 1,000 runs of the cross-validation procedure, median values and 2.5th and 97.5th quantiles of the validation parameters were calculated. REFERENCE TEST: GFR measurement by (51)Cr-EDTA clearance. RESULTS: The BCM model predicted 98% within ±30% of reference GFR and 66% within ±10%, which was higher than for any other model. The weight model predicted 97.5% within ±30% of reference GFR and 62% within ±10%. The BCM model had the highest R(2) and the smallest root mean square error. LIMITATIONS: Included only 9 children with GFR <60 mL/min/1.73 m(2). Lack of independent validation cohort. CONCLUSIONS: The novel BCM model predicts GFR with higher accuracy than previously published models. The weight model is almost as accurate as the BCM model and allows for GFR estimation without knowledge of BCM. However, endogenous methods are still not sufficiently accurate to replace exogenous markers when GFR must be determined with high accuracy.

Precision and within- and between-day variation of bioimpedance parameters in children aged 2-14 years.

BACKGROUND & AIMS: Bioimpedance spectroscopy (BIS) offers the possibility to perform rapid estimates of fluid distribution and body composition. Few studies, however, have addressed the precision and biological variation in a pediatric population. Our objectives were to evaluate precision, variation within- and between-days for the BIS-determined parameters total body fluid, extra-cellular fluid, intra-cellular fluid, body cell mass, fat-free mass, extra-cellular resistance, intra-cellular resistance and percentage body fat using a Xitron 4200. METHODS: All 133 children (81 boys, 52 girls; 2.4-14.9 years) had one series measured on day one (precision population). Forty-four children had a second series on day one (within-day sub-population). Thirty-two children had a series measured on the next day (between-day sub-population). Each measurement series consisted of three repeated measurements. A linear mixed model was used for statistical analysis. RESULTS: The precision was 0.3-0.8% in children ≥6 years and 0.5-2.4% in children <6 years with a statistically significant difference between the two age-groups (p<0.001). Within-day variation was 1.1-2.8% and between-day variation 2.4-5.7%. Total variation and reference change values are reported. CONCLUSION: The Xitron 4200 has a very good but age-dependent precision. The median value of three repeated measurements is recommended in order to avoid incorrect measurements.

Comparison of within- and between-subject variation of serum cystatin C and serum creatinine in children aged 2-13 years.

BACKGROUND: Previously, data on both the within-subject (SD(I)) and the between-subject (SD(G)) variation of cystatin C in children has not been reported. Thus, this study aimed to determine this biological variation including analytical variation (SD(A)) of both cystatin C and creatinine to characterize the two analytes as renal function markers in children. METHODS: On two consecutive days blood samples for duplicate analysis of cystatin C (nephelometric, Dade Behring) and creatinine (enzymatic, Roche) were obtained from 30 children (11 females and 19 males, mean age 8.3 range 2-13 years) referred for GFR measurements by (51)Cr-EDTA clearance. For determination of the between-subject variation only children with normal GFR (n=21) were included. Data were adjusted for the well known age-related increase in creatinine. RESULTS: The results are given as coefficients of variation. The within-subject variations were identical for both analytes (6.4%). The between-subject variation was 11.1% for cystatin C and 28.4% for creatinine, though decreasing to 20.1% after adjusting for age. The analytical variation was 1.7% and 2.5% for cystatin C and creatinine, respectively. The index of individuality (IOI = SD(I)/SD(G)) was 0.65 for cystatin C and 0.25 for creatinine, though increasing to 0.36 after age-adjustment. CONCLUSION: The within-subject variation was identical and low for cystatin C and creatinine suggesting that the two are equally suitable for serial monitoring of renal function in children. Based on the low IOI neither analyte, however, seems suitable as a screening marker of renal function in a healthy population of children using population-based reference intervals.

Reassessment of a classical single injection 51Cr-EDTA clearance method for determination of renal function in children and adults. Part II: Empirically determined relationships between total and one-pool clearance.

BACKGROUND: The one-pool or slope-intercept technique is widely used when determining total (51)Cr-EDTA plasma clearance (Cl). The one-pool clearance (Cl(1)), which always exceeds Cl, has mostly been corrected to Cl by multiplication by a constant factor = 0.80, suggested by Chantler (CH(0.80)), or by using a second-order polynomial originally proposed by Brøchner-Mortensen (BM) and later recommended by the British Nuclear Medicine Society (BM(BNMS)). Theoretical considerations indicate that the CH correction gives a systematic overestimate of Cl, whereas the BM correction may underestimate Cl at high values. OBJECTIVE: To assess the accuracy of Cl as estimated from Cl (1) corrected either by CH(0.80) or by second-order polynomials. MATERIAL AND METHODS: Cl(ref) was determined in 149 subjects (M/F/children: 71/46/32) from a complete plasma curve followed for 4-5 h after injection of (51)Cr-EDTA (range of Cl(ref) : 8-183 mL/min/1.73 m(2)). Cl(est) was determined from Cl(1) subsequently corrected by CH(0.80) and four second-order polynomials. RESULTS: Using CH(0.80) correction, Cl(est) underestimated Cl(ref) (by a maximum of 20%) at Cl(ref) values less than about 100 mL/min/1.73 m(2) in children and 130 mL/min/1.73 m(2) in adults. At higher clearance levels, Cl(ref) was increasingly overestimated. Taking the BM(BNMS) correction as representative of second-order polynomials, Cl(est) increasingly underestimated Cl(ref) at high levels, the error being 10% at a Cl(ref) value of about 175 mL/min/1.73 m(2). CONCLUSIONS: We suggest that the tested correction equations are replaced by the given common correction equation based on the "true" relationship between Cl(1) and Cl thoroughly described in part I of this study.

Measuring glomerular filtration rate in children; can cystatin C replace established methods? A review.

Our aim was to evaluate published methods that use serum cystatin C (s-CysC) for measuring glomerular filtration rate (GFR) in children and to discuss advantages and limitations of s-CysC and of established GFR methods. A comprehensive literature review of clinical studies in children evaluating s-CysC or CysC-based formulas and plasma creatinine or creatinine-based formulas against an exogenous reference method using receiver operating characteristics (ROC) curves or Bland-Altman plots is presented. The comparison of s-CysC with plasma creatinine indicated that s-CysC was superior to plasma creatinine in five of 13 studies; four studies showed no difference, and, in four studies, no statistical comparison was made. Comparison of s-CysC and the Schwartz formula showed that s-CysC was superior to the Schwartz formula in two of seven studies; two studies demonstrated no difference, and, in one study, the Schwartz formula was superior to s-CysC. In two studies no statistical comparison was made. The CysC-based prediction equations all had high accuracy but low agreement when compared with a reference GFR, in the range of 30-40% at best. S-CysC is most likely superior to plasma creatinine and at least equal to creatinine-based formulas. CysC-based prediction equations are at least as good as creatinine-based formulas but cannot replace exogenous methods.

Reassessment of a classical single injection 51Cr-EDTA clearance method for determination of renal function in children and adults. Part I: Analytically correct relationship between total and one-pool clearance.

BACKGROUND: Total plasma clearance of (51)Cr-EDTA, Cl, is widely used as a measure of GFR. Commonly, only the final part of the plasma concentration curve is measured, and a one-pool clearance (slope-intercept clearance), Cl(1), is computed. Empirically determined second-order polynomials of the general form Cl = b x Cl(1) + c x Cl(1)(2) are usually used to estimate Cl from a measured Cl(1). However, theoretical considerations indicate that such corrections underestimate Cl at high values. AIMS: To derive an analytically correct relationship between Cl and Cl(1) and determine the parameters involved for children and adults. MATERIAL AND METHODS: Cl was determined in 149 subjects (M/F/children: 71/46/32) from a complete plasma concentration curve followed for 4-5 h after injection of (51)Cr-EDTA (range of clearance: 8-183 mL/min/1.73 m(2)). Plasma volume, PV and the "missing" area under the plasma fraction curve, a (minutes), not used for determination of Cl(1), were measured. RESULTS: The true relationship between Cl and Cl(1) is given by Cl = Cl(1)/(1 + f x Cl(1)), where f = a/PV. For men, women and children alike, the equation f = 0.0032 x BSA(-1.3) was applicable (BSA = body surface area in m(2)). Estimation errors on clearance were within +/-8% for adults and +/-13% for children (95% limits of agreement). CONCLUSIONS: The true relationship between Cl and Cl(1) of (51)Cr-EDTA is given, resulting in a common correction equation applicable for children and adults. The new equation has better mathematical behaviour than quadratic equations on very high values of clearance and takes into account dependence on body size.

Preoperative dual-phase parathyroid imaging with tc-99m-sestamibi: accuracy and reproducibility of the pinhole collimator with and without oblique images.

BACKGROUND: Previously, we have found that the additional use of a pinhole collimator in parathyroid scintigraphy resulted in a decrease in the number of incorrect side localizations and an increase in reproducibility compared with that of using a parallel-hole collimator alone. PURPOSE: The aim was to investigate whether the addition of anterior oblique views to parathyroid scintigraphy (PS) with a pinhole collimator could further enhance the diagnostic ability and reproducibility. The level of preoperative parathyroid hormone (PTH) as a potential predictor of the usefulness of the supplementary views was also studied. METHOD AND MATERIAL: Forty-seven patients with primary hyperparathyroidism (HPT) underwent dual-phase PS using a combined protocol with parallel-hole and pinhole collimators. The pinhole collimator was used in the anterior as well as right and left anterior oblique positions. Thyroid pertechnetate scans were undertaken in the same positions. Two observers assessed the images independently. RESULTS: By adding oblique views, the gain in correct side localization occurred in all cases but one was seen in patients with rapid washout. The level of PTH could not predict these patients. The observer agreement on correct side localizations rose significantly from 81% to 94%. CONCLUSION: The addition of oblique views to the imaging protocol using the pinhole collimator for parathyroid and thyroid scintigraphy in primary HPT results in an increase in observer agreement and the number of correct side localizations in patients with rapid washout of MIBI. The preoperative level of PTH cannot, however, predict these patients.

Kidney function during and after withdrawal of long-term irbesartan treatment in patients with type 2 diabetes and microalbuminuria.

OBJECTIVE: Irbesartan is renoprotective in patients with type 2 diabetes and microalbuminuria. Whether the observed reduction in microalbuminuria is reversible (hemodynamic) or persistent (glomerular structural/biochemical normalization) after prolonged antihypertensive treatment is unknown. Therefore, the present substudy of the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study (IRMA-2) investigated the reversibility of kidney function changes after withdrawal of 2 years' antihypertensive treatment. RESEARCH DESIGN AND METHODS: The substudy included 133 hypertensive type 2 diabetic patients with persistent microalbuminuria in IRMA-2, randomized to double-masked treatment with either placebo, irbesartan 150 mg, or irbesartan 300 mg o.d. for 2 years. Arterial blood pressure, overnight urinary albumin excretion rate, and glomerular filtration rate (GFR) were determined repeatedly. RESULTS: Baseline characteristics were similar in the placebo, irbesartan 150-mg, and irbesartan 300-mg groups. At the end of the study, mean arterial blood pressure (MABP) was similarly lowered to 105 +/- 2 (mean +/- SE), 103 +/- 2, and 102 +/- 2 mmHg, respectively (P < 0.05 versus baseline), and urinary albumin excretion rate reduced by 8% (-16 to 27) (NS), 34% (95% CI 8-53), and 60% (46-70) (P < 0.05). Rates of decline in GFR were 1.3 +/- 0.7, 1.2 +/- 0.7, and 1.0 +/- 0.8 ml. min(-1). 1.73 m(-2) per month, respectively, during the initial 3 months of the study and 0.3 +/- 0.1, 0.3 +/- 0.1, and 0.4 +/- 0.1 ml. min(-1). 1.73 m(-2) per month in the remaining study period. One month after withdrawal of all antihypertensive medication, MABP remained unchanged in the placebo group, 105 +/- 2 mmHg, but increased significantly in the irbesartan groups, to 109 +/- 2 and 108 +/- 2 mmHg, respectively. Compared with baseline, urinary albumin excretion rate was increased by 14% (-17 to 54) in the placebo group and by 11% (-26 to 65) in the irbesartan 150-mg group but was persistently reduced by 47% (24-73) in the irbesartan 300-mg group (P < 0.05). GFR levels increased to baseline values in the placebo group and approached initial levels in irbesartan groups. CONCLUSIONS: Persistent reduction of microalbuminuria after withdrawal of all antihypertensive treatment suggests that high-dose irbesartan treatment confers long-term renoprotective effects.