Anthropometric Prediction of Total Body Water in Children Who Are on Pediatric Peritoneal Dialysis
Bruce Z. Morgenstern*,
Elke Wühl,
K. Sreekumaran Nair,
Bradley A. Warady and
Franz Schaefer
* Division of Pediatric Nephrology, Phoenix Children’s Hospital, Phoenix, Arizona; Division of Pediatric Nephrology, University Hospital for Pediatric and Adolescent Medicine, University of Heidelberg, Heidelberg, Germany; Division of Endocrinology, Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota; and Section of Pediatric Nephrology, Children’s Mercy Hospital, Kansas City, Missouri
Address correspondence to: Dr. Bruce Z. Morgenstern, Division of Pediatric Nephrology, Phoenix Children’s Hospital, 1919 East Thomas Road, Phoenix, AZ 85016. Phone: 602-546-4700; Fax: 602-546-4701; E-mail: bmorgenstern{at}mayo.edu
Received for publication May 31, 2005.
Accepted for publication October 20, 2005.
Accurate estimation of total body water (TBW) is a criticalcomponent of dialysis prescription in peritoneal dialysis (PD).Gold-standard isotope dilution techniques are laborious andcostly; therefore, anthropometric prediction equations thatare based on height and weight are commonly used to estimateTBW. Equations have been established in healthy populations,but their validity is unclear in children who undergo PD, inwhom altered states of hydration and other confounding alterationsin normal physiology, particularly retarded growth and pubertaldelay, may exist. TBW was measured by heavy water (H2O18 orD2O) dilution in 64 pediatric patients who were aged 1 mo to23 yr and receiving chronic PD in the United States and Germanyto establish and validate population-specific anthropometricTBW prediction equations and to compare the predictive powerof these equations with formulas that have been establishedin healthy children. The best-fitting equations are as follows:For boys, TBW = 0.10 x (HtWt)0.68 – 0.37 x weight; forgirls, TBW = 0.14 x (HtWt)0.64 – 0.35 x weight. The heightx weight parameter also predicts body surface area (BSA). Theseequations can be simplified, with slightly less precision, tothe following: For boys, TBW = 20.88 x BSA – 4.29; forgirls, TBW = 16.92 x BSA – 1.81. TBW is predicted withoutsystematic deviations and equally well in boys and girls, NorthAmerican and European, obese and nonobese, growth-retarded andnormally sized, and pre- and postpubertal children. In contrast,previous anthropometric equations that were derived from healthychildren systematically overpredicted TBW and were less precisein this pediatric PD population. In summary, a new set of anthropometricTBW prediction equations that are suited specifically for usein pediatric PD patients have been provided.
The accurate determination of total body water (TBW) is a criticalcomponent of the dialysis prescription and measurement of thedelivered dialysis dose. Urea kinetic modeling is a key underpinningto dialysis prescription. An estimate of the urea distributionspace (V) is required to calculate normalized urea clearance,i.e., Kt/V (1) for patients who are on peritoneal dialysis (PD)using these models. The urea distribution space, V, is assumedto be the same as TBW. Accurate measurement of TBW requiressophisticated measurement techniques, such as isotope dilutionmeasurements (2), which are costly and time-consuming and, hence,not suitable for routine clinical practice. TBW therefore usuallyis estimated from anthropometric measurements.
The Kidney Disease Outcomes Quality Initiative PD adequacy guidelinesrecommend the use of the formulas of Mellits and Cheek (1) toestimate V in children who are on PD. These formulas are basedon heavy water dilution studies that were performed in healthychildren and estimate TBW using a child’s height, weight,and gender (3). Recently, isotope dilution–derived TBWdata that were obtained in healthy neonates and infants wereadded to the original data set of Mellits and Cheek, and a newset of anthropometric prediction equations were proposed (4).In these equations, a new anthropometric parameter height timesweight (HtWt) that correlates linearly with TBW when both valuesare log-transformed was introduced (4). Estimates from the newerformulas are somewhat more accurate for infants but are stillbased on data that were obtained in healthy children.
In the PD population, disorders of growth and body compositionare common and superimposed on large variations of fluid status.Because direct measures of TBW in children who are on PD usingthe "gold standard" assays involving heavy water have not beenreported in large cohorts of children (5,6), it is unknown whetherthe anthropometric prediction equations that have been establishedin healthy children hold true in this population. Hence, theobjectives of this study were to (1) measure TBW in childrenincident to maintenance PD using heavy water, (2) develop andvalidate population-specific (i.e., children on PD) formulasto estimate TBW on the basis of anthropometric measurements,and (3) compare the accuracy and the precision of the formulaswith those of prediction equations that have been establishedin healthy children.
Patients
This study represents a collaboration between the PediatricPeritoneal Dialysis Study Consortium (PPDSC), a multicenterorganization of pediatric PD centers (centers listed at theend of the article) and the University of Heidelberg Schoolof Medicine (Heidelberg, Germany). Infants, children, and adolescentswere eligible. The US cohort of children was studied within90 d of initiation of PD. The German children had been on PDfor a mean of 28.8 ± 32.4 mo. All patients were in astable state of hydration at time of assessment without overtedema. In no case was the study performed within 30 d of anepisode of peritonitis.
The study protocol was designed in adherence to the declarationof Helsinki and approved by local Institutional Review Boardsor Ethical Committees. Written informed consent was obtainedfrom all parents, and informed consent or assent was obtainedfrom the patients as appropriate.
Heavy Water Dilution Studies
For the PPDSC cohort, H2O18 (Isotec; Sigma-Aldrich, St. Louis,MO) was used to determine TBW, and D2O (Merck, Darmstadt, Germany)was used in the study that was performed in Heidelberg. H2O18was administered as a 10% solution in a volume equal to thesquare root of the patient’s weight divided by 70 kg,multiplied by 30.4 (the volume of a 10% solution needed fora 70-kg individual). In the Heidelberg cohort, 1 g of D2O (purity99.9%) per kilogram of body weight was administered. The childrenthen drank another 30 ml of water out of the glass or bottlethat was used to administer the dose to ensure complete deliveryof the heavy water. Blood samples were obtained immediatelybefore and 4 h after administration. Plasma H2O18 concentrationwas determined at the Mayo Clinic Core Biomedical Mass SpectrometryLaboratory by mass spectrometry, and plasma D2O was determinedby vacuum distillation and Fourier-transformed infrared spectroscopyas described previously (5). The coefficient of variation (CV)of both methods is <0.5%. TBW was calculated by the plasmaenrichment of heavy water relative to the mass administered,with a correction factor of 1.01 for the H2O18 space and of1.04 for the D2O space to account for isotope sequestration(7,8). Because heavy water has previously been demonstratedto equilibrate fully with the intraperitoneal volume over 4h (5), the intraperitoneal volume was subtracted from the TBWcalculated to yield the final result.
Statistical Analyses
The PPDSC sample was used to establish the principal relationshipbetween height and weight and TBW. Log-transformed TBW datawere regressed against the log-transformed anthropometric parameter,HtWt, which correlates linearly in studies that have been performedon healthy children (4). A linear relationship between HtWtand TBW was also found in this population. The residuals inthe best fitting single-term equation were analyzed for remainingsystematic effects by anthropometric variables or gender. Thisanalysis disclosed the need for constructing gender-specificequations with inclusion of a linear correction factor accountingfor body mass. The PPDSC and the Heidelberg samples were pooledinto a single cohort to enhance the validity of the resultinggender-specific equations.
The resulting final prediction equations were internally cross-validatedby separate reapplication to population subsets—The NorthAmerican and the German patients, boys and girls, growth-retarded(height SD score [SDS] <–2) versus patients of normalheight, patients with increased (>1) versus normal BMI SDS—and,finally, to random subsets that comprised two thirds and onethird of the entire cohort, respectively. Height and body massindex SDS (BMI z scores) were calculated using nation-specificnorms (9,10). BMI SDS were calculated using the LMS method,to account for the non-Gaussian distribution of BMI in the population(11).
The precision of the prediction equations was expressed by theroot mean square error (RMSE), i.e., the square root of thesum of squared differences between the observed and the predictedvalues divided by the number of patients studied. The smallerthe RMSE, the greater is the accuracy of the equation. Thereis no absolute criterion value for an RMSE that indicates successful(12) validation. Because a wide range of TBW was studied, theRMSE was also expressed by the CV, i.e., RMSE divided by themean value of the dependent variable. The accuracy of the predictionwas expressed by the mean difference between calculated andmeasured TBW values.
In addition, regression analyses were performed and Bland-Altmanplots were generated to quantify the residual error inherentin the different anthropometric prediction methods available.Apart from the new formulas established here, estimates examinedwere TBW = 0.6 x body weight (13), the Mellits and Cheek equations(1), and the newer series of anthropometric predictive equationsdescribed earlier (hereinafter called "New Healthy") (4).
Finally, because the HtWt parameter appears as a parameter ina common formula that is used to estimate body surface area(BSA = [(HtWt)/3600]0.5) (14), the relationships between TBWformulas and BSA were explored, and the accuracy of that relationshipwas similarly assessed.
Statistical analysis was performed using Microsoft Excel version11.1.1 (Microsoft Corp., Redmond, WA) and SAS version 8.2 (SAS,Cary, NC). Pearson product moment correlation coefficients werecalculated for univariate analysis of associations between continuousvariables and paired t test for comparison of between-groupdifferences. The best fitting formula for TBW was obtained bythe NLIN procedure in the SAS package.
Demographics Table 1 shows the basic clinical characteristics of the patientswho were studied in the PPDSC centers and in Heidelberg. Thirty-fourchildren (16 girls, 18 boys) who were new to maintenance PDwere studied in the United States. The children had mean ageof 8.2 yr (range 1.5 mo to 19 yr). The 30 children from Heidelbergcomprised nine girls and 21 boys, with a mean age of 12.6 yr(range 14 mo to 23 yr). The German children were older (P <0.01), were taller (P < 0.05), and had a lower BMI z score(P < 0.0001) than the PPDSC group (Table 1).
Table 1. Basic demographics of the patient cohorts used for validation of prediction equationa
The mean (±SD) TBW for the groups was 16.9 ± 9.5L (range 2.4 to 40.5 L). The TBW averaged 56.8% (±10.1%)of body weight (Table 1). The percentage of body weight representingTBW was inversely related to age (r = –0.29, P < 0.05),height (r = –0.35, P = 0.005), weight (r = –0.49,P < 0.0001; Figure 1), and BMI (r = –0.57, P < 0.0001).Whereas % TBW did not differ in boys and girls who were youngerthan 10 yr, adolescent girls had significantly less body waterper unit of weight (49.2 ± 10.3%) than adolescent boys(56.1 ± 5.6%; P < 0.05).
Figure 1. Variation of tissue hydration (percentage of total body water [% TBW]) in 64 pediatric peritoneal dialysis (PD) patients who were aged 1 mo to 23 yr. [utrif], boys; , girls. % TBW was inversely related to body mass (r = –0.49, P < 0.0001).
Development and Validation of TBW Prediction Equation
The 34 patients of the PPDSC cohort were used to establish abest fitting anthropometric prediction equation. Regressionanalysis verified a tight linear relationship of the log-transformedmeasured TBW values with the log-transformed Ht x Wt product(R2 = 0.96, P < 0.0001). Back-transformation of this relationshipyielded the following allometric equation:
The RMSE of the estimates based on Equation 1 was 3.02 L relativeto the measured data (CV 20.1%). Inclusion of the Heidelbergsample in the validation cohort confirmed the close log-linearrelationship between HtWt and TBW (R2 = 0.93, RMSE 2.60, CV15.4%, P < 0.0001).
Bland-Altman analysis of the residual variation in the relationshipbetween measured and predicted TBW disclosed that the predictiveaccuracy and precision were inversely related to absolute bodymass, with systematic overestimation of TBW in pubertal boysand underestimation in pubertal girls. Therefore, gender-specificprediction equations were established. Inclusion of a linearcorrection factor for body mass further improved the goodnessof fit for both genders. All patients were used to determinethe coefficients resulting in the following best fitting equations:
By these equations, TBW was predicted with R2 = 0.95, a mean(±SD) difference(estimated – expected TBW) of 0.001± 2.15 L, and an RMSE of 2.17 L (CV 12.8%; Figure 2,Table 2). Equations 2a and 2b were reapplied to estimate TBWin the US and the German cohorts, in randomly selected subsetsthat comprised two thirds and one third of the total cohort,in boys and girls as well as in subsets that comprised patientswith high versus low BMI SDS or low versus normal height SDS(Table 2). TBW was predicted equally well in all selected subpopulations,without any systematic deviations or imprecisions. Equations 2aand 2b are arithmetically complex relationships. Nomogramsfor children of different genders and body sizes based on theseequations are presented in Appendix 1.
Figure 2. Comparison of calculated TBW by new anthropometric equations (Equations 2a and 2b) with measured TBW (R2 = 0.95, P < 0.0001). , US children; •, German children.
Table 2. Accuracy and precision of anthropometric TBW prediction by Equations 2a and 2b in subsets of validation cohorta
Effect of Hydration on Anthropometric TBW Prediction
Alterations of hydration status are an inevitable source oferror in anthropometric TBW prediction using only height andweight. To assess the effect of altered hydration on the precisionof our prediction model, we categorized the cohort into fractionalTBW quintiles (Figure 3). Patients with a trend toward overhydrationwill cluster in the top quintile (i.e., those 20% of patientswith the highest TBW content relative to body weight), and thosewith relative fluid depletion will cluster in the bottom quintile.TBW prediction was not affected systematically in the second,third, and fourth quintiles but tended to be low in the highestand high in the lowest quintile. The median prediction errorwas –16.9% in the top quintile and 9.8% in the bottomquintile, suggesting a moderate bias to TBW prediction at theextremes of hydration.
Figure 3. Relative estimation error (expressed as regression residual divided by measured TBW) of Equations 2a and 2b according to % TBW quintiles. "1" denotes bottom, "5" top quintile of fractional TBW within the cohort. Dot and error bars denote mean ± SD.
Predictive Accuracy and Precision of Anthropometric Equations in Children on PD
The comparative analysis of the new PD-specific pediatric predictionequations with two published anthropometric prediction equationsthat were derived from healthy children and another common approximationassuming TBW as a constant fraction of 60% of body weight isgiven in Table 3 and Figure 4. The three alternative equationshad an inferior predictive precision in this pediatric PD cohort,with RMSE ranging from 2.37 to 3.4 L (CV 13.9 to 20.2%). Moreover,TBW was systematically overestimated with each of the equations(P < 0.0001 for each comparison).
Figure 4. Bland-Altman plots of measured TBW versus difference between measured and estimated TBW using Equations 2a and 2b (A), Mellits and Cheek equations (B), the "New Healthy" equations (C), and 0.6 x body weight (D).
Relationship of TBW to BSA
The TBW estimates using Equation 1 correlated linearly withBSA estimates using the Gehan (15) formula (BSA = 0.02350 xheight0.42246 x weight0.51456); the correlation led to the followingformulas:
where BSA is in m2 (r2 = 0.94, P < 0.0001). These equationsestimate TBW with a mean (SD) difference of –0.16 (2.3)L. The RMSE is 2.36 L, which corresponds to a CV of 13.9%. Usingthe simplified BSA formula (BSA = [(HtWt)/3600]0.5) (14), theresulting correlations are similar:
In this article, we have established a pair of population-specificequations that allows one to predict with acceptable accuracyand precision TBW in boys and girls on who are chronic PD. Theequations should prove useful in standardizing PD prescriptionaccording to the size of the distribution space of urea andother small molecules.
An accurate determination of TBW in patients who are on dialysisis necessary to assess fluid status and to calculate delivereddialysis dose by Kt/V and has been used in adult and pediatricstudies to assess body composition and nutritional status (12,16,17).Estimation of TBW by simple formulas, such as 0.6 times bodyweight, or by formulas that are based on data derived from healthypatients is inaccurate, with an inferior predictive precisionaccounting for approximately 10% wider error ranges than predictionderived with the new population-specific equations. Such errorsmay have clinical relevance in the pediatric PD population (18).
The importance of using an adequate TBW approximation procedureis illustrated by the wide range of the TBW fraction observedin the pediatric PD population in this and previous studies(5,6). This wide variability is explained by both physiologic(developmental) changes and disease-related alterations of hydration:The TBW fraction decreases across childhood, particularly duringthe infant years (13). During puberty, differential changesof body composition are induced by male and female sex steroidproduction (19). Whereas boys experience a marked increase inlean body mass, girls tend to accumulate more fat than leantissue, resulting in reciprocal changes of the water compartment.These changes held through in the pediatric PD population studiedhere; fractional TBW was inversely correlated with age and wasconsistently lower in female compared with male adolescents.
Disorders of hydration and nutritional status, which may bedisease related, are superimposed on these physiologic/developmentalcauses of TBW variability in childhood. These are related inpart to the difficulty of maintaining a neutral fluid balancein children who are on PD, whose capacity to excrete water isaltered and where fluid retention and excessive fluid lossescommonly occur. Alterations of the nutritional state are commonin these children as well, including malnutrition or obesity.In fact, children who are on supplemental tube feeding are frequentlysuspected to have both increased fat tissue deposition and wastingof lean body mass. The combined effects of alterations in fluidand metabolic balance may have little overall impact on bodyweight or the BMI but major effects on the distribution of hydratedand nonhydrated tissue compartments.
While none of the patients in this study displayed signs andsymptoms of grossly altered hydration, subclinical disordersof fluid status could not be ruled out. We attempted to quantifythe effect of abnormal hydration on anthropometric TBW predictionby defining % TBW quintiles. TBW tended to be underpredictedin the top quintile and to be overpredicted in the lowest quintileof fractional TBW distribution. This was expected because anthropometricprediction is based on the assumption of a constant proportionof water and water-free tissues. The prediction error at theends of the hydration spectrum was moderate in quantitativeterms, averaging at –16.9% in the 20% of patients withthe highest fractional TBW and at 9.8% in the quintile withthe lowest TBW content.
Tracer dilution studies are not likely to be performed as aroutine in all children who are on maintenance PD because ofthe complexity of the procedure and the expense of the tracer.More precise TBW estimates can be achieved in children who areon PD by obtaining additional anthropometric information usingbioelectrical impedance (BIA) or skinfold measurements (5).With either of these techniques, the CV of the TBW estimationcan be reduced to approximately 8.5% as compared with 12.9%with the equations presented here. Studies in adult patientsconfirm the usefulness of BIA-based prediction equations inpredicting TBW (12,16,17). However, because BIA is not availablein most dialysis units, the anthropometric equations establishedhere should serve as an acceptable compromise between optimalpredictive power and routine clinical applicability.
The relationship between TBW and BSA has been noted before (4,20,21).In adult PD patients, this finding has been particularly relevantin obese patients (20). The finding has been explained by thefact that in most formulas to calculate BSA, an increase inweight with no change in height results in a proportionallysmaller increase of BSA. The formulas for BSA therefore areless subject to the impact of overweight (22). Our previousreanalysis of data obtained in healthy children suggested thatBSA may well be a better parameter than height or weight aloneeven on those who are not obese (4). Certainly, the linear relationshipbetween TBW and BSA in children who are on PD described above(Equations 3a and 3b) facilitates an easier estimation of TBWcompared with the more arithmetically complex Equations 2a and2b. However, it must be pointed out that adopting the "easier"estimation of TBW from BSA will necessarily result in a slightloss of precision. The RMSE of Equations 3a and 3b is 2.36 L(CV 13.9%) compared with 2.18 L (CV 12.9%) using Equations 2aand 2b. To facilitate use of the more precise estimates, wehave developed nomograms (see Appendix 1).
In this work, we took account of the complex changes in bodycomposition during childhood by constructing gender-specificprediction equations that comprised an allometric height x weightterm with an additional linear component. This strategy resultedin an improved quality of the anthropometric estimation. Wewere able to reduce RMSE to 2.18 L (CV 12.9%). This level ofprecision will result in a clinically acceptable error rangeof the ultimate Kt/V estimate; e.g., in a 10-yr-old child withan estimated TBW of 17 L, a calculated weekly Kt/V urea of 2.0will correspond to a "true" Kt/V between 1.8 and 2.2 (±1SD) in 68% of the measurements. Internal cross-validation ofthe equations confirmed a very robust, reliable performancein subsets of the cohort. TBW was predicted equally well andwithout systematic deviations in obese and nonobese, tall andshort, and North American and German children, as well as inrandomly selected subsets of the cohort. Although the predictivepower of the new equations was superior to previous anthropometricformulas that were derived in healthy children, it should bekept in mind that even with the optimized formula, the 95% confidenceinterval for TBW predictions is as high as ±4.4 L. Becauseof the physiologic and pathologic variability of body compositionand fluid balance outlined above, it may be impossible to reducefurther this residual variance of estimation if only heightand weight data are available (20,23–25).
In summary, we have verified that anthropometric equations thatare based on healthy individuals can provide only limited approximationsof body composition in a diseased population, such as childrenwho are receiving chronic PD; truly useful equations shouldbe constructed and validated in the specific population of interest.We provide such a set of anthropometric TBW prediction equations,which permit superior precision and accuracy compared with previousformulas that were established in healthy children. The recommendationto use the equations of Mellits and Cheek (1) to determine TBW,or V, in children who are on maintenance PD is now able to berevised.
TBW Nomograms for children of typical heights and weights. Extremesof either height or weight have been eliminated. These dataare based on Equations 2a and 2b (see text). For each gender,table a is for smaller children.
These data were presented in abstract form at the Annual ScientificMeetings of the American Society of Nephrology in 2000 (October13 to 16, Toronto, Canada) and 2002 (November 1 to 4, Philadelphia,PA).
Participating centers from the PPDSC: S. Watkins MD, Children’sHospital Seattle, Seattle, WA; B. Warady, MD, Children’sMercy Hospital, Kansas City, MO; G. Lerner, MD, Children’sHospital Los Angeles, Los Angeles, CA; B. Morgenstern, MD, MayoClinic, Rochester, MN; A. Quan, MD, Children’s Hospital,Dallas, TX; A. Neu, MD, Johns Hopkins University, Baltimore,MD; P. Brophy MD, C.S. Mott Children’s Hospital, Ann Arbor,MI; E. Brewer, MD, Texas Children’s Hospital, Houston,TX.
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Abstract
Introduction
, girls. % TBW was inversely related to body mass (r = –0.49, P < 0.0001).
