Hepcidin and disordered mineral metabolism in chronic kidney disease.

BACKGROUND: Hepcidin regulates iron homeostasis by blocking iron absorption from the gut and iron release from macrophage and hepatocyte stores. Hepcidin levels are elevated in kidney failure and thus, are thought to contribute to dysregulation of iron homeostasis in chronic kidney disease (CKD). However, the primary factors associated with increased hepcidin levels in CKD patients have not been well-defined. In particular, few studies examined the relationships between hepcidin and disorders of mineral metabolism, which are among the earliest and most common complications of CKD. METHODS: We examined the associations between hepcidin, iron indexes, and markers of mineral metabolism in 125 patients from across the spectrum of pre-dialysis CKD. Bioactive hepcidin levels were measured in serum samples by competitive ELISA. RESULTS: Hepcidin was inversely associated with eGFR and linearly associated with ferritin (p < 0.001 for both). In unadjusted analyses, increased serum phosphate and parathyroid hormone (PTH) and decreased 1,25-dihydroxyvitamin D (1,25(OH)2D) levels were associated with increased hepcidin. When examined in forward stepwise regression analysis, higher phosphate and PTH levels and lower 1,25(OH)2D and FGF23 levels were selected as independent predictors of higher hepcidin levels, whereas there was no association between eGFR and hepcidin. CONCLUSIONS: Abnormalities in phosphate and vitamin D metabolism were associated with increased hepcidin levels independently of eGFR in CKD patients. These findings suggest that disorders of mineral metabolism may promote increased hepcidin secretion in CKD. Whether inflammation mediates these associations requires further study.

Racial differences in the relationship between vitamin D, bone mineral density, and parathyroid hormone in the National Health and Nutrition Examination Survey.

UNLABELLED: It is unclear whether optimal levels of 25-hydroxyvitamin D (25(OH)D) in whites are the same as in minorities. In adult participants of NHANES, the relationships between 25(OH)D, bone mineral density (BMD), and parathyroid hormone (PTH) differed in blacks as compared to whites and Mexican-Americans, suggesting that optimal 25(OH)D levels for bone and mineral metabolism may differ by race. INTRODUCTION: Blacks and Hispanics have lower 25-hydroxyvitamin D concentrations than whites. However, it is unclear whether 25(OH)D levels considered "optimal" for bone and mineral metabolism in whites are the same as those in minority populations. METHODS: We examined the relationships between 25(OH)D and parathyroid hormone in 8,415 adult participants (25% black and 24% Mexican-American) in the National Health and Nutrition Examination Surveys 2003-2004 and 2005-2006; and between 25(OH)D and bone mineral density in 4,206 adult participants (24% black and 24% Mexican-American) in the 2003-2004 sample. RESULTS: Blacks and Mexican-Americans had significantly lower 25(OH)D and higher PTH concentrations than whites (P < 0.01 for both). BMD significantly decreased (P < 0.01) as serum 25(OH)D and calcium intake declined among whites and Mexican-Americans, but not among blacks (P = 0.2). The impact of vitamin D deficiency (25(OH)D ≤ 20 ng/ml) on PTH levels was modified by race/ethnicity (P for interaction, 0.001). Whereas inverse relationships between 25(OH)D and PTH were observed above and below a 25(OH)D level of 20 ng/ml in whites and Mexican-Americans, an inverse association between 25(OH)D and PTH was only observed below this threshold in blacks, with the slope of the relationship being essentially flat (P = 0.7) above this cut-point, suggesting that PTH may be maximally suppressed at lower 25(OH)D levels in blacks than in whites or Mexican-Americans. CONCLUSIONS: The relationships between 25(OH)D, BMD, and PTH may differ by race among US adults. Whether race-specific ranges of optimal vitamin D are needed to appropriately evaluate the adequacy of vitamin D stores in minorities requires further study.

Prevalence and severity of disordered mineral metabolism in Blacks with chronic kidney disease.

Disorders of mineral metabolism develop early in chronic kidney disease, but it appears that Blacks with stage-5 disease have more severe secondary hyperparathyroidism than other races. We measured levels of parathyroid hormone, calcium, phosphorus, 25-hydroxyvitamin D (25D) and 1,25-dihydroxyvitamin D (1,25D) in 227 Black and 1633 non-Black participants in the SEEK study, a multi-center cohort of patients with early chronic kidney disease. Overall, Blacks had similar 1,25D levels compared with non-Blacks, but significantly lower levels of 25D with higher levels of calcium, phosphorus, and parathyroid hormone, and were significantly more likely to have hyperphosphatemia than non-Blacks. In multivariable analyses adjusted for age, gender, estimated glomerular filtration rate, body mass index, and diabetes, Blacks had significantly lower 25D and higher parathyroid hormone levels than non-Blacks, with the latter parameter remaining significant after further adjustment for calcium, phosphorus, 25D, and 1,25D. The association between Black race and secondary hyperparathyroidism, independent of known risk factors, suggests that novel mechanisms contribute to secondary hyperparathyroidism in Blacks with chronic kidney disease.

CACP, encoding a secreted proteoglycan, is mutated in camptodactyly-arthropathy-coxa vara-pericarditis syndrome.

Altered growth and function of synoviocytes, the intimal cells which line joint cavities and tendon sheaths, occur in a number of skeletal diseases. Hyperplasia of synoviocytes is found in both rheumatoid arthritis and osteoarthritis, despite differences in the underlying aetiologies of the two disorders. We have studied the autosomal recessive disorder camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP; MIM 208250) to identify biological pathways that lead to synoviocyte hyperplasia, the principal pathological feature of this syndrome. Using a positional-candidate approach, we identified mutations in a gene (CACP) encoding a secreted proteoglycan as the cause of CACP. The CACP protein, which has previously been identified as both 'megakaryocyte stimulating factor precursor' and 'superficial zone protein', contains domains that have homology to somatomedin B, heparin-binding proteins, mucins and haemopexins. In addition to expression in joint synovium and cartilage, CACP is expressed in non-skeletal tissues including liver and pericardium. The similarity of CACP sequence to that of other protein families and the expression of CACP in non-skeletal tissues suggest it may have diverse biological activities.

[Digestibility, protein value and protein requirements of diets based on plantain/bean and cassava/bean in young adults]. / Digestibilidad, valor proteínico y necesidades de proteína de dietas a base de plátano/frijol y de yuca/frijol en jóvenes adultos.

Information is provided on the nitrogen intake for nitrogen equilibrium in young human adults fed a cassava/bean diet and a plantain/bean diet. Ten individuals participating in each study ingested levels of 0, 0.2, 0.4 and 0.6 g protein/kg/day at a constant energy level (45 kcal/kg/day), using the short-term nitrogen balance method with multiple intakes. Even with intakes of 105.7 and 117.4 mg N/kg/day for the cassava/bean and plantain/bean diets, the experimental subjects did not reach a positive balance. The protein digestibility of the diets was low, as had been confirmed previously for beans alone: 55.7% for the cassava/bean study and 50.4% for plantains/beans. The average quantity of nitrogen intake required to reach nitrogen equilibrium for the cassava/bean diet was 114.3 mg N/kg/day and for the plantain/bean diet, 111.9 mg N/kg/day. In the case of the cassava/bean diet, the variability was 81.3 to 172.4, and for plantain/beans, 83.6 to 219.3 mg/kg/day. In four of the five individuals who participated in both studies, the nitrogen intake required to reach nitrogen equilibrium was greater when fed the diet based on plantain/beans than when fed the cassava/beans diet. These data support the assertion that the protein requirement is not a simple figure. Individual variability is so great that, as has been suggested, it is necessary to add two standard deviations to the average figure to cover 97.5% of the population. The results of this investigation support the need to increase protein digestibility and protein quality of beans, since this is a food of major importance for large population segments in the developing countries.