Myocardial hypertrophy, impaired renal function, and adverse effects on bone remodeling were associated with hyperphosphatemia and were not corrected by PTH replacement. Although no vascular calcification was observed in this model, we cannot rule out an adverse effect of hyperphosphatemia on the vascular bed. Our finding underscores the importance of phosphorus control in reducing morbidity and mortality in CRF patients.
Osteoporosis in hemodialysis patients is associated with high morbidity and mortality and, although extensively studied by noninvasive methods, has never been assessed through bone biopsy. The aim of this study was to use histomorphometry to evaluate osteoporosis and identify factors related to its development in hemodialysis patients. We conducted a cross-sectional study involving 98 patients (35 women and 63 men; mean age: 48.4 +/- 13 years) on hemodialysis for 36.9 +/- 24.7 months. Patients were submitted to transiliac bone biopsy with double tetracycline labeling. The bone metabolism factors ionized calcium, phosphorus, bone alkaline phosphatase, deoxypyridinoline, intact parathyroid hormone, and 25(OH) vitamin D were evaluated, as were the bone remodeling cytokines osteoprotegerin (OPG), soluble receptor-activator of NF-kappabeta ligand (sRANKL) and tumor necrosis factor-alpha (TNF)alpha. Osteoporosis was defined as trabecular bone volume (BV/TV) greater than 1 s.d. below normal (men <17.4%; women <14.7%). Forty-five patients (46%) presented osteoporosis, which was correlated with white race. We found BV/TV to correlate with age, OPG/sRANKL ratio, TNFalpha levels, and length of amenorrhea. In multiple regression analysis adjusted for sex and age, length of amenorrhea, white race, and OPG/sRANKL ratio were independent determinants of BV/TV. Histomorphometric analysis demonstrated that osteoporotic patients presented normal eroded surface and low bone formation rate (BFR/BS). Osteoporosis is prevalent in hemodialysis patients. Low BFR/BS could be involved in its development, even when bone resorption is normal. Cytokines may also play a role as may traditional risk factors such as advanced age, hypogonadism, and white race.
Osteocytes respond to kidney damage by increasing production of secreted factors important to bone and mineral metabolism. These circulating proteins include the antianabolic factor, sclerostin, and the phosphaturic hormone, fibroblast growth factor 23 (FGF23). Elevated sclerostin levels correlate with increased FGF23, localized reduction in Wnt/β-catenin signaling in the skeleton and reduced osteoblast differentiation/activity. Decreased Wnt/β-catenin signaling occurs regardless of the overall changes in bone formation rates, suggesting that a reduction in the anabolic response may be a common feature of renal bone disorders but additional mechanisms may contribute to the diversity of osteodystrophy phenotypes. Recent preclinical studies support this hypothesis, as treatment with antisclerostin antibodies improved bone quality in the context of low but not high turnover renal osteodystrophy. Sclerostin also appears in the circulation suggesting additional roles outside the skeleton in normal and disease states. In patients with chronic kidney disease (CKD), serum levels are elevated several fold relative to healthy individuals. Emerging data suggest that these changes are associated with increased fracture rates but the relationship between sclerostin and cardiovascular disease is unclear. Additional epidemiologic studies that examine stage specific and patient sub-populations are needed to assess whether sclerostin elevations influence comorbidities associated with CKD.
Parathyroid hormone (PTH) has an important role in the maintenance of serum calcium levels. It activates renal 1α-hydroxylase and increases the synthesis of the active form of vitamin D (1,25[OH]2D3). PTH promotes calcium release from the bone and enhances tubular calcium resorption through direct action on these sites. Hallmarks of secondary hyperparathyroidism associated with chronic kidney disease (CKD) include increase in serum fibroblast growth factor 23 (FGF-23), reduction in renal 1,25[OH]2D3 production with a decline in its serum levels, decrease in intestinal calcium absorption, and, at later stages, hyperphosphatemia and high levels of PTH. In this paper, we aim to critically discuss severe CKD-related hyperparathyroidism, in which PTH, through calcium-dependent and -independent mechanisms, leads to harmful effects and manifestations of the uremic syndrome, such as bone loss, skin and soft tissue calcification, cardiomyopathy, immunodeficiency, impairment of erythropoiesis, increase of energy expenditure, and muscle weakness.
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