Muscle torque relative to cross-sectional area and the functional muscle-bone unit in children and adolescents with chronic disease.

Measures of muscle mass or size are often used as surrogates of forces acting on bone. However, chronic diseases may be associated with abnormal muscle force relative to muscle size. The muscle-bone unit was examined in 64 children and adolescents with new-onset Crohn's disease (CD), 54 with chronic kidney disease (CKD), 51 treated with glucocorticoids for nephrotic syndrome (NS), and 264 healthy controls. Muscle torque was assessed by isometric ankle dynamometry. Calf muscle cross-sectional area (CSA) and tibia cortical section modulus (Zp) were assessed by quantitative CT. Log-linear regression was used to determine the relations among muscle CSA, muscle torque, and Zp, adjusted for tibia length, age, Tanner stage, sex, and race. Muscle CSA and muscle torque-relative-to-muscle CSA were significantly lower than controls in advanced CKD (CSA -8.7%, p = 0.01; torque -22.9%, p < 0.001) and moderate-to-severe CD (CSA -14.1%, p < 0.001; torque -7.6%, p = 0.05), but not in NS. Zp was 11.5% lower in advanced CKD (p = 0.005) compared to controls, and this deficit was attenuated to 6.7% (p = 0.05) with adjustment for muscle CSA. With additional adjustment for muscle torque and body weight, Zp was 5.9% lower and the difference with controls was no longer significant (p = 0.09). In participants with moderate-to-severe CD, Zp was 6.8% greater than predicted (p = 0.01) given muscle CSA and torque deficits (R(2) = 0.92), likely due to acute muscle loss in newly-diagnosed patients. Zp did not differ in NS, compared with controls. In conclusion, muscle torque relative to muscle CSA was significantly lower in CKD and CD, compared with controls, and was independently associated with Zp. Future studies are needed to determine if abnormal muscle strength contributes to progressive bone deficits in chronic disease, independent of muscle area. © 2014 American Society for Bone and Mineral Research.

Changes in bone structure and the muscle-bone unit in children with chronic kidney disease.

The impact of pediatric chronic kidney disease (CKD) on acquisition of volumetric bone mineral density (BMD) and cortical dimensions is lacking. To address this issue, we obtained tibia quantitative computed tomography scans from 103 patients aged 5-21 years with CKD (26 on dialysis) at baseline and 12 months later. Gender, ethnicity, tibia length, and/or age-specific Z-scores were generated for trabecular and cortical BMD, cortical area, periosteal and endosteal circumference, and muscle area based on over 700 reference subjects. Muscle area, cortical area, and periosteal and endosteal Z-scores were significantly lower at baseline compared with the reference cohort. Cortical BMD, cortical area, and periosteal Z-scores all exhibited a significant further decrease over 12 months. Higher parathyroid hormone levels were associated with significantly greater increases in trabecular BMD and decreases in cortical BMD in the younger patients (significant interaction terms for trabecular BMD and cortical BMD). The estimated glomerular filtration rate was not associated with changes in BMD Z-scores independent of parathyroid hormone. Changes in muscle and cortical area were significantly and positively associated in control subjects but not in CKD patients. Thus, children and adolescents with CKD have progressive cortical bone deficits related to secondary hyperparathyroidism and potential impairment of the functional muscle-bone unit. Interventions are needed to enhance bone accrual in childhood-onset CKD.

Bone density and cortical structure after pediatric renal transplantation.

The impact of renal transplantation on trabecular and cortical bone mineral density (BMD) and cortical structure is unknown. We obtained quantitative computed tomography scans of the tibia in pediatric renal transplant recipients at transplantation and 3, 6, and 12 months; 58 recipients completed at least two visits. We used more than 700 reference participants to generate Z-scores for trabecular BMD, cortical BMD, section modulus (a summary measure of cortical dimensions and strength), and muscle and fat area. At baseline, compared with reference participants, renal transplant recipients had significantly lower mean section modulus and muscle area; trabecular BMD was significantly greater than reference participants only in transplant recipients younger than 13 years. After transplantation, trabecular BMD decreased significantly in association with greater glucocorticoid exposure. Cortical BMD increased significantly in association with greater glucocorticoid exposure and greater decreases in parathyroid hormone levels. Muscle and fat area both increased significantly, but section modulus did not improve. At 12 months, transplantation associated with significantly lower section modulus and greater fat area compared with reference participants. Muscle area and cortical BMD did not differ significantly between transplant recipients and reference participants. Trabecular BMD was no longer significantly elevated in younger recipients and was low in older recipients. Pediatric renal transplant associated with persistent deficits in section modulus, despite recovery of muscle, and low trabecular BMD in older recipients. Future studies should determine the implications of these data on fracture risk and identify strategies to improve bone density and structure.

Vitamin D deficiency is common in children and adolescents with chronic kidney disease.

Here we determined if vitamin D deficiency is more common in children with chronic kidney disease compared to healthy children. In addition, we sought to identify disease-specific risk factors for this deficiency, as well as its metabolic consequences. We found that nearly half of 182 patients (ages 5 to 21) with kidney disease (stages 2 to 5) and a third of age-matched 276 healthy children were 25-hydroxyvitamin D deficient (<20 ng/ml). The risk of deficiency was significantly greater in advanced disease. Focal segmental glomerulosclerosis and low albumin were significantly associated with lower 25-hydroxyvitamin D, which, in turn, was associated with significantly higher intact parathyroid hormone levels. We found that 25-hydroxyvitamin D levels were positively associated with 1,25-dihydroxyvitamin D, the relationship being greatest in advanced disease (significant interaction), and inversely related to those of inflammatory markers C-reactive protein and IL-6. The association with C-reactive protein persisted when adjusted for the severity of kidney disease. Thus, lower 25-hydroxyvitamin D may contribute to hyperparathyroidism, inflammation, and lower 1,25-dihydroxyvitamin D in children and adolescents, especially those with advanced kidney disease.

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.

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.