For histological evaluation of retinasepon-embedded mind of flies were sectioned stained with toluidineblue as described

To compare bone marker levels of patients with and without rhGH treatment with the best possible exclusion of confounding factors, the group of patients with rhGH treatment were compared to an untreated control group matched individually for age, sex, eGFR, CRP, and iPTH. Of the original cohort, the control group was selected out of 186 patients who were not treated with rhGH and were living in the same countries as children with rhGH treatment. Matching of rhGH treated and untreated patients was performed using SAS 9.2. Matches were available for 41 out of 42 rhGH treated patients. Post hoc testing for significant differences of matching variables and additional confounding factors between groups was performed. Paired t-tests were applied to test for differences of bone marker levels between the matched groups. Statistical analyses were performed using SAS 9.2 and R. A p-value _ 0.05 was considered statistically significant. This is the first comprehensive study of novel circulating markers of bone activity performed in a large, representative cohort of children with moderate to severe CKD. Within the pediatric age range, bone formation rate and bone turnover are essentially based on the developmental state of the skeleton. Relating our results to recently established age-specific reference values allowed us to account for the physiological variability of bone markers during childhood. We demonstrated abnormal distributions of the osteoblast marker BAP, the osteoclast marker TRAP5b and the osteocyte markers cFGF-23 and sclerostin, compatible with a major alteration of bone turnover in this population. Furthermore, we observed significant changes of the bone marker profile in children undergoing rhGH treatment. Normalizing BAP and TRAP5B plasma levels for age and sex in this large pediatric cohort with CKD stage 3 to 5, we observed a clear increase of BAP and a slight but significant increase of TRAP5B levels. This finding is compatible with a preferential high bone turnover in this patient group. A small association of BAP SDS with eGFR emerged in multivariate but not univariate analysis, indicating a higher bone turnover rate in earlier CKD stages. However, the association was weak, suggesting a predominant role of factors other than renal function. When controlling for age, sex, eGFR and underlying renal disease the main predictors of increased BAP and TRAP5b levels were low CRP and high iPTH levels. The negative association of BAP and TRAP5b with CRP may indicate a link between inflammation and reduced bone turnover or adynamic bone disease independent of the underlying renal disease, whereas the independent positive association with iPTH supports a potential role of these bone markers for the CX-4945 assessment of high bone turnover. In adult CKD patients sclerostin levels increased progressively with advanced CKD. However, in mice with progressive CKD sclerostin levels were found increased in early disease but decreased in advanced renal failure. In keeping with that study we found overall reduced sclerostin levels in this cohort of patients with moderate to severe CKD. There is also experimental and clinical evidence of sclerostin suppression by PTH. Accordingly, low sclerostin levels were predictive of high bone turnover in adults with CKD. Our results confirm an inverse relationship of sclerostin and iPTH, adding to the notion that the osteoanabolic effects of iPTH may be partially related to the inhibition of sclerostin release. Also, the bulk of sclerostin in healthy bone is released by osteocytes deep within the bone matrix whereas osteocytes near zones of bone remodeling produce little sclerostin. Consistent with the observed high BAP and TRAP5b levels suggesting a high bone turnover state, the low plasma sclerostin concentrations in this cohort might indicate a relative preponderance of zones of bone remodeling over compartments with mature osteocytes and constant sclerostin production. Little is known to date about the interaction of sclerostin with vitamin D metabolism. Increased 1,25-dihydroxy-vitamin D hydroxylase activity has recently been demonstrated in sclerostin knockout mice. The independent positive association of 25OHD and sclerostin levels observed here might reflect the impact of vitamin D status on mineralized bone mass. Since the majority of children in this cohort were vitamin D insufficient or deficient, the decreased sclerostin levels might in part be explained by impaired vitamin D action. Plasma FGF-23 levels are age-dependent and increase early in the course of CKD prior to any abnormalities of serum phosphorus, calcium or PTH. They correlate well with FGF- 23 synthesis in the bone, as demonstrated in a study of 32 pediatric and young adult CKD patients.

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