The complexity of chronic kidney disease–mineral and bone disorder across stages of chronic kidney disease

Abstract

Chronic Kidney Disease (CKD)-Mineral and Bone Disorder (CKD-MBD) is a complex disease that is not completely understood. However, some factors secreted by the osteocytes might play an important role in its pathophysiology. Therefore, we evaluated the bone expression of proteins in a group of patients with CKD 2-3, CKD 4, and CKD 5 on dialysis and healthy individuals. We also tested several bone remodeling markers, and correlated these levels with bone biopsy findings. As expected, as serum calcium decreased, serum phosphate, alkaline phosphatase, fibroblast growth factor-23 (FGF-23), parathyroid hormone, and osteoprotegerin increased, as CKD progressed. Additionally, there was a gradual increase in bone resorption associated with a decrease in bone formation and impairment in bone mineralization. Bone expression of sclerostin and parathyroid hormone receptor-1 seemed to be increased in earlier stages of CKD, whereas FGF-23 and phosphorylated β-catenin had increased expression in the late stages of CKD, although all these proteins were elevated relative to healthy individuals. Immunohistochemical studies showed that FGF-23 and sclerostin did not co-localize, suggesting that distinct osteocytes produce these proteins. Moreover, there was a good correlation between serum levels and bone expression of FGF-23. Thus, our studies help define the complex mechanism of bone and mineral metabolism in patients with CKD. Linkage of serum markers to bone expression of specific proteins may facilitate our understanding and management of this disease.

Fibroblast Growth Factor 23 Genotype and Cardiovascular Disease in Patients Undergoing Hemodialysis

“…This may indicate that currently tested SNPs in FGF23 do not modulate serum levels of FGF23. Furthermore, serum concentrations of intact FGF23 in patients receiving dialysis can increase 400-fold from CKD stage 2-5, due not only to increased secretion from bone but also altered regulation and clearance [7,30,31]. The striking elevations and wide distribution of FGF23 among patients receiving dialysis may have masked associations of any of the FGF23 SNPs and serum concentrations of FGF23.…”

TGF-Beta Signaling in Bone with Chronic Kidney Disease

“…Because sclerostin expression in bone increases in early CKD [119,120,121], the skeleton is speculated to be the source of increased circulating sclerostin in CKD. High sclerostin levels may reflect increased osteocyte numbers and skeletal mass [122,123].…”

“…Since AGEs accumulate in the CKD condition [131], the effect of AGE-3 on SOST expression through increased TGF-β may contribute to the high SOST level. Bone sclerostin expression is diminished in late-stage CKD compared to that in early-stage CKD [119,121]. Stage-dependent sclerostin expression may be reflected by the degree of TGF-β stimulation, because the PTH level is elevated in the late-stage, while the accumulation of AGEs occurs in all stages of CKD.…”

Análise da expressão gênica e de proteínas reguladoras do fósforo e da remodelação óssea: efeitos do transplante renal e do ácido zoledrônico

“…Após a realização da biópsia, o fragmento ósseo foi dividido em duas partes: a primeira, após inclusão em metil-metacrilato, sem descalcificação, foi utilizada para análise de histomorfometria e imunohistoquimica 62 ; e a segunda foi congelada imediatamente em nitrogênio líquido e em seguida estocada em freezer a -80°C em solução de Trizol™, para posterior processamento (homogeneização), dosagem proteica e avaliação de expressão gênica. …”

“…Publicação recente do nosso grupo já tinha demonstrado elevação da expressão de esclerostina óssea, beta-catenina total e fosforilada e FGF-23, através da imunohistoquimica, em estágios iniciais de DRC quando comparados a controles normais. O aumento da expressão da esclerostina, em adultos, ocorre de forma mais precoce que o FGF-23 62,70 . Pelo nosso conhecimento, este é o primeiro estudo que avalia o metabolismo ósseo, através de vários biomarcadores, em sua dosagem sérica, no conteúdo ósseo e pela expressão gênica no mesmo momento.…”