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  • Larry Gilbert posted an update 2 weeks, 1 day ago

    FGF-23 is mainly expressed by osteocytes of the trabecular periphery. In dialyzed children circulating FGF-23 levels were found related to the process of osteoid maturation and mineralization time. FGF-23 is highly expressed at sites of new bone formation and appears to regulate osteoblast matrix mineralization in an age-dependent INCB28060 fashion. In a study of predialysis children FGF-23, but not PTH or serum phosphorus, independently predicted bone formation. All this evidence suggests a direct role of FGF-23 in bone formation and mineralization. While our study cannot provide insights into the bone morphology of children with CKD, it adds to the current state of knowledge the important observation that FGF-23 levels are associated with relative height in growing children. We also noted that patients with metabolic acidosis tend to exhibit lower FGF-23 at a given eGFR and serum phosphorus level. This association might indicate a novel mechanistic link between metabolic acdosis and mineral-bone disorder in CKD. This interpretation is supported by a randomized trial in dialyzed children investigating the effect of rhGH treatment on bone formation, where children receiving rhGH exhibited a higher bone formation rate than untreated children irrespective of bone histology at baseline. Evidence for increased bone formation rate and bone mass from exposure to IGF1 also comes from conditions such as acromegaly and rhGH treated children receiving long-term corticosteroid therapy. Sclerostin is a potent inhibitor of Wnt signaling, which plays an important role during bone formation. The finding that serum sclerostin levels were significantly higher with a distribution matching that of healthy children, suggests that rhGH might play a role in the regulation of bone formation via this pathway. We were unable to confirm the findings of a small study in GH deficient children showing an increase of cFGF-23 during rhGH supplementation therapy ; small changes in cFGF-23 might be overshadowed by the overall increase of cFGF-23 in CKD. Taken together, our findings support a major osteoanabolic effect of rhGH treatment in children with CKD. In conclusion, in a large cohort of children with predialysis CKD we found important associations of serum bone biomarkers to patient characteristics, traditional markers of bone metabolism and linear growth. Our study benefited from a large sample size, the controlled observational study design and the application of age-specific reference values. However, a limitation results from the lack of a direct assessment of bone status by biopsy or skeletal imaging studies such as DEXA, pqCT or MRI. Also, it should be emphasized that the observed associations cumulatively explained only 10-20% of the overall variation of bone marker concentrations and 10-24% of the variance of growth indicators. Hence, while our study is informative regarding important biological regulators of bone metabolism and growth, other major sources of variation, including the impact of genetic disposition, remain to be explored. We hope that our findings will prompt further evaluation of these biomarkers including bone imaging techniques and bone histomorphometry to further validate their usefulness in the assessment and therapeutic monitoring of bone metabolism in children with CKD. Until the emergence and approval of an effective interferon -free regimen, pegylated interferon -α will remain an integral part of the treatment of HCV-4. Newer treatment regimens, including direct acting antivirals in combination with PEG-INF-α and ribavirin are more effective against HCV genotype 1, with higher rates of sustained virological response in treatment-naïve patients reaching 75%. However, these regimens are associated with poor response in prior null responders especially those with cirrhosis and are challenged by new adverse events and non-eligibility for many patients. At present, these new regimens remain largely untested in HCV-4 populations, and the current national standard of care therapy comprises PEG-IFN-α along with RBV, with associated SVR rates of more than 60%. INF-based regimens are compromised with high pill burden and undesirable adverse effects ; therefore, there is a desperate need to predict failure of response. MicroRNAs are small ~22 nucleotide non-coding RNAs that deregulate gene expression by mRNA degradation, or translational repression. Cellular miRNAs can regulate diverse domains, including proliferation, differentiation, immune reaction, and tumorigenesis. Circulating miRNAs display consistent profiles between healthy individuals and significantly altered expression in diseases; however, the functions of these miRNAs remain to be elucidated.