Early Skeletal and Biochemical Alterations in Pediatric Chronic Kidney Disease

Wesseling‐Perry, Katherine; Pereira, Renata C.; Tseng, Chi‐Hong; Elashoff, Robert M.; Zaritsky, Joshua J.; Yadin, Ora; Sahney, Shobha; Gales, Barbara; Jüppner, Harald; Salusky, Isidro B.

doi:10.2215/cjn.05940611

Cited by 146 publications

(140 citation statements)

References 33 publications

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“…Given the demonstrated association of lower serum calcium with defective mineralization 36 and that the majority of phosphate binder use in CKiD was calcium-based, we hypothesize that the protective effect may be due to calcium supplementation; indeed, substituting use of a calcium-containing binder and/or vitamin was similarly protective in the final multivariable Cox model, with a 63% lower fracture risk. This is supportive of our prior finding that serum calcium was an independent correlate of cortical BMD, particularly in the growing skeleton.…”

Section: Discussionmentioning

confidence: 94%

“…36 In children on peritoneal dialysis, this mineralization defect persisted after therapy with active vitamin D. 37 In children with pre-dialysis CKD, lower serum calcium and higher PTH concentrations were associated with defective mineralization. 36 Taken together, these findings suggest that hyperparathyroidism contributes to increased fracture risk in children with CKD via impaired mineralization.…”

Section: Discussionmentioning

confidence: 99%

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Fracture Burden and Risk Factors in Childhood CKD

Denburg

Kumar

Jemielita

et al. 2016

Journal of the American Society of Nephrology

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107

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Childhood chronic kidney disease (CHD) poses multiple threats to bone accrual; however, the associated fracture risk is not well characterized. This prospective cohort study included 537 CKD in Children (CKiD) participants. Fracture histories were obtained at baseline, at years 1, 3, and 5 through November 1, 2009, and annually thereafter. We used Cox regression analysis of first incident fracture to evaluate potential correlates of fracture risk. At enrollment, median age was 11 years, and 16% of patients reported a prior fracture. Over a median of 3.9 years, 43 males and 24 females sustained incident fractures, corresponding to 395 (95% confidence interval [95% CI], 293-533) and 323 (95% CI, 216-481) fractures per 10,000 person-years, respectively. These rates were 2-to 3-fold higher than published general population rates. The only gender difference in fracture risk was a 2.6-fold higher risk in males aged $15 years (570/10,000 person-years, adjusted P=0.04). In multivariable analysis, advanced pubertal stage, greater height Z-score, difficulty walking, and higher average log-transformed parathyroid hormone level were independently associated with greater fracture risk (all P#0.04). Phosphate binder treatment (predominantly calcium-based) was associated with lower fracture risk (hazard ratio, 0.37; 95% CI, P=0.03). Participation in more than one team sport was associated with higher risk (hazard ratio, 4.87; 95% CI, 2.21-10.75; P,0.001). In conclusion, children with CKD have a high burden of fracture. Regarding modifiable factors, higher average parathyroid hormone level was associated with greater risk of fracture, whereas phosphate binder use was protective in this cohort.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Fracture Burden and Risk Factors in Childhood CKD

Denburg

Kumar

Jemielita

et al. 2016

Journal of the American Society of Nephrology

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107

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“…Skeletal Wnt inhibition and increased sclerostin are found in early CKD, 15 although remodeling rates may not be reduced in early CKD. The frequencies of decreased bone formation rates in early CKD stages 2-4 are controversial, ranging from 0% to 50%, [52][53][54] and may be age-related. In animal models of early CKD caused by polycystic kidney disease and Alport's disease, normal or elevated modeling rates were observed as osteodystrophy was detected, despite findings of decreased nuclear b-catenin in osteocytes and elevated sclerostin levels.…”

Section: Discussionmentioning

confidence: 99%

CKD-Induced Wingless/Integration1 Inhibitors and Phosphorus Cause the CKD–Mineral and Bone Disorder

Fang¹,

Ginsberg

Seifert

et al. 2014

Journal of the American Society of Nephrology

149

186

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In chronic kidney disease, vascular calcification, renal osteodystrophy, and phosphate contribute substantially to cardiovascular risk and are components of CKD-mineral and bone disorder (CKD-MBD). The cause of this syndrome is unknown. Additionally, no therapy addresses cardiovascular risk in CKD. In its inception, CKD-MBD is characterized by osteodystrophy, vascular calcification, and stimulation of osteocyte secretion. We tested the hypothesis that increased production of circulating factors by diseased kidneys causes the CKD-MBD in diabetic mice subjected to renal injury to induce stage 2 CKD (CKD-2 mice). Compared with non-CKD diabetic controls, CKD-2 mice showed increased renal production of Wnt inhibitor family members and higher levels of circulating Dickkopf-1 (Dkk1), sclerostin, and secreted klotho. Neutralization of Dkk1 in CKD-2 mice by administration of a monoclonal antibody after renal injury stimulated bone formation rates, corrected the osteodystrophy, and prevented CKD-stimulated vascular calcification. Mechanistically, neutralization of Dkk1 suppressed aortic expression of the osteoblastic transcription factor Runx2, increased expression of vascular smooth muscle protein 22-a, and restored aortic expression of klotho. Neutralization of Dkk1 did not affect the elevated plasma levels of osteocytic fibroblast growth factor 23 but decreased the elevated levels of sclerostin. Phosphate binder therapy restored plasma fibroblast growth factor 23 levels but had no effect on vascular calcification or osteodystrophy. The combination of the Dkk1 antibody and phosphate binder therapy completely treated the CKD-MBD. These results show that circulating Wnt inhibitors are involved in the pathogenesis of CKD-MBD and that the combination of Dkk1 neutralization and phosphate binding may have therapeutic potential for this disorder. CKD is a pandemic affecting 26 million Americans in its early stages. 1 CKD is associated with high rates of cardiovascular mortality, making it much more likely that affected individuals will sustain cardiovascular morbidity, including death, than reach end stage kidney disease that requires RRT.

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“…In children, however, information is limited regarding the prevalence and determinants of FGF23 excess and 1,25(OH) 2 D deficiency across the spectrum of predialysis CKD and their potential association with adverse renal and cardiovascular outcomes. Prior singlecenter studies of FGF23 and mineral metabolism in childhood CKD have been limited by small sample size (18,19), heterogeneous study populations that include dialysis and transplant patients (5,20), and imprecise estimates of GFR (21,22).…”

Section: Introductionmentioning

confidence: 99%

Disordered FGF23 and Mineral Metabolism in Children with CKD

Portale

Wolf

Jüppner

et al. 2014

Clinical Journal of the American Society of Nephrology

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132

101

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SummaryBackground and objectives In children with CKD, information is limited regarding the prevalence and determinants of fibroblast growth factor 23 excess and 1,25-dihyroxyvitamin D deficiency across the spectrum of predialysis CKD. This study characterized circulating concentrations of fibroblast growth factor 23 and 1,25-dihyroxyvitamin D, and investigated their interrelationships and associations with GFR and secondary hyperparathyroidism in children with CKD who were enrolled in the Chronic Kidney Disease in Children observational cohort study.Design, setting, participants, & measurements Plasma fibroblast growth factor 23 concentrations and determinants of mineral metabolism were measured in 464 children ages 1-16 years with predialysis CKD. GFR was measured by plasma disappearance of iohexol in 70% of participants and estimated by the Chronic Kidney Disease in Children estimating equation using serum creatinine and cystatin C concentrations in the remainder of the participants. Participants were grouped according to CKD stage and by 10-ml/min categories of GFR.Results Median GFR for the cohort was 45 ml/min per 1.73 m 2 (interquartile range=33-57; range=15-109). Plasma fibroblast growth factor 23 concentration was above the normal range in 67% of participants (with higher levels observed among participants with lower GFR) before higher levels of serum parathyroid hormone and phosphorus were observed. Plasma fibroblast growth factor 23 levels were 34% higher in participants with glomerular disease than in participants with nonglomerular disease, despite similar GFR. Serum phosphorus levels, adjusted for age, were significantly lower at GFR of 60-69 ml/min per 1.73 m 2 than higher GFR, but thereafter they became higher in parallel with fibroblast growth factor 23 as GFR declined. Serum 1,25-dihyroxyvitamin D concentrations were lower in those participants with low GFR values, high fibroblast growth factor 23 levels, 25-hydroxyvitamin D deficiency, and proteinuria. Secondary hyperparathyroidism was present in 55% of participants with GFR,50 ml/min per 1.73 m 2 .Conclusion In children with predialysis CKD, high plasma fibroblast growth factor 23 is the earliest detectable abnormality in mineral metabolism, and levels are highest in glomerular diseases.

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Early Skeletal and Biochemical Alterations in Pediatric Chronic Kidney Disease

Cited by 146 publications

References 33 publications

Fracture Burden and Risk Factors in Childhood CKD

Fracture Burden and Risk Factors in Childhood CKD

CKD-Induced Wingless/Integration1 Inhibitors and Phosphorus Cause the CKD–Mineral and Bone Disorder

Disordered FGF23 and Mineral Metabolism in Children with CKD

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