Bethany J. Foster

Whole body BMC in pediatric Crohn disease: Independent effects of altered growth, maturation, and body composition

Whole body BMC was assessed in 104 children and young adults with CD and 233 healthy controls. CD was associated with significant deficits in BMC and lean mass, relative to height. Adjustment for lean mass eliminated the bone deficit in CD. Steroid exposure was associated with short stature but not bone deficits relative to height.

A Novel Method of Expressing Left Ventricular Mass Relative to Body Size in Children

Background— Left ventricular (LV) hypertrophy (LVH) in children is widely defined as a left ventricular mass index (LVMI, g/m2.7) >95th percentile. However, LVMI increases with decreasing height in young children; thus, the 95th percentile LVMI will depend on the height distribution of the reference population. The objective of this study was to compare the performance of a novel method of expressing LV mass relative to body size (centile curves) with the LVMI method. Methods and Results— LV mass was estimated by M-mode echocardiography in 440 healthy nonobese reference children (birth to 21 years) and 239 children at risk for LVH; the LVMI was calculated for all children. Three samples of 270 children, each with different height distributions, were drawn from the reference population. A sample-specific 95th percentile LVMI was determined for each reference sample. At-risk children were classified as having LVH or not based on each sample-specific 95th percentile. Four LV mass-for-height centile curves were constructed with the Cole lambda-mu-sigma method and data from each reference sample. At-risk children were each assigned an LV mass-for-height percentile with these curves and were reclassified as having LVH if LV mass-for-height was >95th percentile. The centile method provided a stable estimate of the proportion of at-risk children with LVH regardless of reference group, whereas proportion estimates varied significantly depending on the reference population when the LVMI method was used. Conclusions— LV mass-for-height centile curves are superior to LVMI as a method of normalizing LV mass to body size in children.

Body-composition alterations consistent with cachexia in children and young adults with Crohn disease

BACKGROUND Crohn disease (CD) in children is associated with low body mass index (BMI), poor growth, and delayed maturation; alterations in lean and fat mass, however, are poorly characterized. OBJECTIVE The objective was to quantify lean and fat mass in children and young adults with CD and in healthy control subjects, relative to height and pubertal maturation. DESIGN This cross-sectional study assessed whole-body lean and fat mass by using dual-energy X-ray absorptiometry in 104 subjects with CD and in 233 healthy control subjects aged 4-25 y. Linear regression was used to determine the effect of CD on body composition and to generate sex-specific SD scores (z scores) for lean and fat mass relative to height. RESULTS Subjects with CD had lower height-for-age and BMI-for-age z scores (P < 0.001 for both) than did control subjects. CD was associated with significant deficits in lean mass after adjustment for height, age, race, and Tanner stage (P = 0.003); deficits in fat mass were not observed. The mean (+/-SD) lean mass-for-height and fat mass-for-height z scores in the subjects with CD were -0.61 +/- 0.92 and -0.04 +/- 0.86, respectively. Within the control group, fat mass-for-height was positively correlated with lean mass-for height (r = 0.41, P < 0.0001); this association was absent in the subjects with CD. CONCLUSIONS Children and young adults with CD had significant deficits in lean mass but preserved fat mass, which is consistent with cachexia. Further research is needed to identify physical activity, nutritional, and antiinflammatory interventions to improve body composition in persons with CD.

Mortality Risk Among Children Initially Treated With Dialysis for End-Stage Kidney Disease, 1990–2010

IMPORTANCE Most children with end-stage kidney disease (ESKD) are treated with dialysis prior to transplant. It is not known whether their outcomes have changed in recent years. OBJECTIVE To determine if all-cause, cardiovascular, and infection-related mortality rates for children and adolescents beginning dialysis improved between 1990 and 2010. DESIGN, SETTING, AND PARTICIPANTS Retrospective cohort study of patients younger than 21 years initially treated with dialysis for ESKD, recorded in the United States Renal Data System between 1990 and 2010. Children with a prior kidney transplant were excluded. We used Cox proportional hazard models to estimate the hazard ratios (HRs) for mortality associated with a 5-year increment in year of ESKD treatment initiation. Primary analyses censored observation at kidney transplant. MAIN OUTCOMES AND MEASURES All-cause, cardiovascular, and infection-related mortality. RESULTS A total of 3450 children younger than 5 years and 19,951 children 5 years or older started dialysis from 1990-2010. Of those younger than 5 years, 705 died during dialysis treatment (98.8/1000 person-years); mortality rates were 112.2 and 83.4 per 1000 person-years in those initiating dialysis in 1990-1994 and 2005-2010, respectively. Of those 5 years and older at treatment initiation, 2270 died during dialysis treatment (38.6/1000 person-years). Their mortality rates were 44.6 and 25.9 per 1000 person-years in those initiating dialysis in 1990-1994 and 2005-2010, respectively. Each 5-year increment in calendar year of dialysis initiation was associated with an adjusted HR of 0.80 (95% CI, 0.75-0.85) among children younger than 5 years at initiation and an HR of 0.88 (95% CI, 0.85-0.92) among those 5 years and older. RESULTS A total of 23,401 children and adolescents who initiated ESKD treatment with dialysis at younger than 21 years between 1990 and 2010 were identified. Crude mortality rates during dialysis treatment were higher among children younger than 5 years at the start of dialysis compared with those who were 5 years and older. Mortality rates for both children and adolescents being treated for ESKD with dialysis decreased significantly between 1990 and 2010. CONCLUSIONS AND RELEVANCE In the United States, there was a substantial decrease in mortality rates over time among children and adolescents initiating ESKD treatment with dialysis between 1990 and 2010. Further research is needed to determine the specific factors responsible for this decrease.

Association between age and graft failure rates in young kidney transplant recipients.

Background. Age at transplant and graft failure risk are associated in young kidney transplant recipients. The risk of graft failure may also vary by current age, irrespective of age at transplant. We sought to estimate age-specific graft failure rates in young kidney transplant recipients and to estimate the relative hazards of graft failure at different ages, compared with at the age of 25 to 29 years. Methods. We evaluated 90,689 patients recorded in the United States Renal Data System database who received a first transplant when younger than 40 years (1988–2009); 18,310 were younger than 21 years at transplant. Time-dependent Cox models with time-varying covariates were used to estimate the association between age (time-dependent) and death-censored graft failure risk, adjusted for time since transplant and other potential confounders. Results. There were 31,857 graft failures over a median follow-up of 5.9 years (interquartile range, 2.5–10.5 years; maximum, 21.8 years). Crude age-specific graft failure rates were highest in 19 year olds (6.6 per 100 person-years). Compared with individuals with the same time since transplant observed at 25 to 29 years of age, death-censored graft failure rates were highest in 17 to 24 year olds (hazard ratio, 1.20; [95% confidence interval 1.13, 1.27] for 17–20 year olds and 1.20 [1.13, 1.26] for 21–24 year olds; both P<0.0001) and lowest in 5 to 12 year olds (hazard ratio, 0.60; [0.53, 0.68] for 5–9 year olds and 0.56 [0.49, 0.64] for 10–12 year olds; both P<0.0001). Conclusion. Among first kidney transplant recipients younger than 40 years, older adolescents and young adults (17–24 years) have the highest risk of graft failure, irrespective of age at transplant.

Change in Mortality Risk Over Time in Young Kidney Transplant Recipients

Mortality risk for kidney transplant recipients may change with increasing accumulated exposure to the “transplantation milieu.” We sought to characterize changes over time in mortality rate and in age‐, sex‐ and race‐standardized mortality ratios (SMR) relative to the general population, and to estimate the association between increasing time since first transplant and mortality risk. A total of 18 911 patients who received a first transplant at <21 years old (1983–2006), and whose data were recorded in the USRDS, were studied. There were 2713 deaths over a median follow‐up of 8.9 (interquartile range 4.0–14.5; maximum 23) years. Among those with graft function, mortality was highest in the first post transplant year; beyond the first year of the first transplant, age‐adjusted mortality rates and SMRs decreased slightly over follow‐up. Cause of death was cardiovascular for 34.6%, infection for 19.5%, malignancy for 5.8%, other for 21.4% and unknown for 18.7%. For every 1‐year time increment after the end of the first post transplant year, age‐adjusted all‐cause and cardiovascular mortality rates fell by 1% (p = 0.06) and 16% (p = 0.007), respectively; infection‐related mortality rate did not change over time (p = 0.5). These results suggest that exposure to the transplantation milieu has no cumulative negative effects on cardiovascular health over the long term.

Association of Chronic Kidney Disease with Muscle Deficits in Children

The effect of chronic kidney disease (CKD) on muscle mass in children, independent of poor growth and delayed maturation, is not well understood. We sought to characterize whole body and regional lean mass (LM) and fat mass (FM) in children and adolescents with CKD and to identify correlates of LM deficits in CKD. We estimated LM and FM from dual energy x-ray absorptiometry scans in 143 children with CKD and 958 controls at two pediatric centers. We expressed whole body, trunk, and leg values of LM and FM as Z-scores relative to height, sitting height, and leg length, respectively, using the controls as the reference. We used multivariable regression models to compare Z-scores in CKD and controls, adjusted for age and maturation, and to identify correlates of LM Z-scores in CKD. Greater CKD severity associated with greater leg LM deficits. Compared with controls, leg LM Z-scores were similar in CKD stages 2 to 3 (difference: 0.02 [95% CI: -0.20, 0.24]; P = 0.8), but were lower in CKD stages 4 to 5 (-0.41 [-0.66, -0.15]; P = 0.002) and dialysis (-1.03 [-1.33, -0.74]; P < 0.0001). Among CKD participants, growth hormone therapy associated with greater leg LM Z-score (0.58 [0.03, 1.13]; P = 0.04), adjusted for CKD severity. Serum albumin, bicarbonate, and markers of inflammation did not associate with LM Z-scores. CKD associated with greater trunk LM and FM, variable whole body LM, and normal leg FM, compared with controls. In conclusion, advanced CKD associates with significant deficits in leg lean mass, indicating skeletal muscle wasting. These data call for prospective studies of interventions to improve muscle mass among children with CKD.

Survival in pediatric dialysis and transplant patients.

BACKGROUND AND OBJECTIVES Long-term follow-up data are few in children with ESRD. We sought to describe long-term survival, assess risk factors for death, and compare survival between two time periods in pediatric ESRD patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We used a population-based retrospective cohort utilizing data from a national organ failure registry and from Canadas universal healthcare system. We included 843 children (ages, 0 to 18) initiating renal replacement therapy from 1992 to 2007 and followed them until death or date of last contact (median follow-up, 6.8 years; interquartile range, 3.0 to 10.6). We assessed risk factors for death and examined cause-specific mortality. RESULTS During 5991 patient-years of follow-up, 107 (12.7%) patients died. Unadjusted cumulative survival for the cohort was: 91.7% (95% CI, 89.8 to 93.7%) at 5 years and 85.8% (95% CI, 82.8 to 88.8%) at 10 years. Among patients commencing dialysis, overall adjusted survival was poorest among those who started dialysis at age <1 year. No secular trends in survival were noted for either dialysis or transplant patients. The proportion of incident patients receiving pre-emptive transplantation increased over time. Pre-emptively transplanted patients did not demonstrate superior adjusted survival compared with those who spent >2 years on dialysis before transplant (hazard ratio, 1.53; 95% CI, 0.63 to 3.67). CONCLUSIONS No significant improvements in survival were observed among ESRD patients over the study period. Time with transplant function had the strongest association with survival. Pre-emptive transplantation was not associated with improved survival in adjusted models.

Development and Validation of a Predictive Equation for Lean Body Mass in Children and Adolescents

Background: Lean body mass (LBM) is not easy to measure directly in the field or clinical setting. Equations to predict LBM from simple anthropometric measures, which account for the differing contributions of fat and lean to body weight at different ages and levels of adiposity, would be useful to both human biologists and clinicians. Aim: To develop and validate equations to predict LBM in children and adolescents across the entire range of the adiposity spectrum. Subjects and methods: Dual energy X-ray absorptiometry was used to measure LBM in 836 healthy children (437 females) and linear regression was used to develop sex-specific equations to estimate LBM from height, weight, age, body mass index (BMI) for age z-score and population ancestry. Equations were validated using bootstrapping methods and in a local independent sample of 332 children and in national data collected by NHANES. Results: The mean difference between measured and predicted LBM was − 0.12% (95% limits of agreement − 11.3% to 8.5%) for males and − 0.14% ( − 11.9% to 10.9%) for females. Equations performed equally well across the entire adiposity spectrum, as estimated by BMI z-score. Validation indicated no over-fitting. LBM was predicted within 5% of measured LBM in the validation sample. Conclusion: The equations estimate LBM accurately from simple anthropometric measures.

Volumetric bone mineral density and bone structure in childhood chronic kidney disease

Chronic kidney disease (CKD) is associated with increased fracture risk and skeletal deformities. The impact of CKD on volumetric bone mineral density (vBMD) and cortical dimensions during growth is unknown. Tibia quantitative computed tomographic scans were obtained in 156 children with CKD [69 stages 2 to 3, 51 stages 4 to 5, and 36 stage 5D (dialysis)] and 831 healthy participants aged 5 to 21 years. Sex‐, race‐, and age‐ or tibia length–specific Z‐scores were generated for trabecular BMD (TrabBMD), cortical BMD (CortBMD), cortical area (CortArea) and endosteal circumference (EndoC). Greater CKD severity was associated with a higher TrabBMD Z‐score in younger participants (p < .001) compared with healthy children; this association was attenuated in older participants (interaction p < .001). Mean CortArea Z‐score was lower (p < .01) in CKD 4–5 [−0.49, 95% confidence interval (CI) −0.80, −0.18)] and CKD 5D (−0.49, 95% CI −0.83, −0.15) compared with healthy children. Among CKD participants, parathyroid hormone (PTH) levels were positively associated with TrabBMD Z‐score (p < .01), and this association was significantly attenuated in older participants (interaction p < .05). Higher levels of PTH and biomarkers of bone formation (bone‐specific alkaline phosphatase) and resorption (serum C‐terminal telopeptide of type 1 collagen) were associated with lower CortBMD and CortArea Z‐scores and greater EndoC Z‐score (r = 0.18–0.36, all p ≤ .02). CortBMD Z‐score was significantly lower in CKD participants with PTH levels above versus below the upper limit of the Kidney Disease Outcome Quality Initiative (KDOQI) CKD stage‐specific target range: −0.46 ± 1.29 versus 0.12 ± 1.14 (p < .01). In summary, childhood CKD and secondary hyperparathyroidism were associated with significant reductions in cortical area and CortBMD and greater TrabBMD in younger children. Future studies are needed to establish the fracture implications of these alterations and to determine if cortical and trabecular abnormalities are reversible.