Interactions of sclerostin with FGF23, soluble klotho and vitamin D in renal transplantation

Relationships of Sclerostin, a bone anti-anabolic protein, with biomarkers of mineral bone disorders in chronic kidney disease are still unsettled, in particular in kidney transplant (KTR). In 80 KTR patients (31F/49M, 54.7±10.3 years) we studied the relationships of serum Sclerostin with eGFR, Calcium, Phosphate, Alkaline Phosphatase (AP), intact Parathyroid hormone (iPTH), soluble alpha-Klotho (sKlotho), intact Fibroblast Growth Factor 23 (iFGF23), 25-hydroxyvitamin D(25D) and 1,25-dihydroxyvitamin D (1,25D). Thirty healthy subjects (35.0±12.4 years, eGFR 109.1±14.1 ml /min/1,73m2) served as control for Sclerostin, iFGF23 and sKlotho. With a median eGFR of 46.3 mL/min/1.73m2 (IQR, 36.2-58.3) our KTR had median Sclerostin levels of 23.7 pmol/L (IQR: 20.8-32.8), not different from controls (26.6 pmol/L, IQR: 22.0-32.2; p = n.s). Sclerostin correlated negatively with AP (r = -.251; p = 0.023) and positively with iFGF23 (r = .227; p = 0.017) and 25D (r = .214; p = 0.025). Age-adjusted multiple regression analysis identified AP and 1,25D as negative and 25D and sKlotho as positive best predictors of Sclerostin. No correlation was evident with eGFR. The negative correlation with AP confirms the direct anti-anabolic role of Sclerostin. The associations either negative or positive with iFGF23, sKlotho, and vitamin D metabolites suggest also a modulatory role in mineral homeostasis. In particular, the associations with iFGF23 (positive) and 1,25D (negative) underline the relevant inhibitory action of Sclerostin on vitamin D activation. In conclusion, Sclerostin levels in KTR are normal and influenced more by bone turnover than by eGFR. Its involvement with other hormones of mineral homeostasis (FGF23/Klotho and Vitamin D) is part of the sophisticated cross-talk between bone and the kidney

In vitro Evaluation of the Calcification Inhibitory Properties of Policosanol, Genistein, and Vitamin D (Reduplaxin®) either Alone or in Combination

Introduction: The process of vascular calcification has severe clinical consequences in a number of diseases, including diabetes, atherosclerosis, and end-stage renal disease. In the present study, we investigated the effect of policosanol (Poli), genistein (Gen), and vitamin D (VitD) separately and in association to evaluate the possible synergistic action on inorganic phosphate (Pi)-induced calcification of vascular smooth muscle cells (VSMCs). Methods: Primary human VSMCs were cultured with either growth medium or growth medium supplemented with calcium and phosphorus (calcification medium) in combination with Poli, Gen, and VitD. Alizarin Red staining, mineralization, and the protein expression of RUNX2 and superoxide dismutase-2 (SOD2) were investigated. Results: All three substances tested were effective at reducing osteogenic differentiation of VSMCs in a dose-dependent manner. Poli+Gen, Poli+VitD, Gen+VitD treatment induced a greater inhibition of calcification and RUNX2 expression compared to single compounds treatments. Moreover, the association of Poli+Gen+VitD (Reduplaxin®) was more effective at inhibiting VSMCs mineralization and preventing the increase in RUNX2 expression induced by calcification medium but not modified SOD2 expression. Conclusions: The association of Pol, Gen, and VitD (Reduplaxin®) has an additive inhibitory effect on the calcification process of VSMCs induced in vitro by a pro-calcifying medium

The effects of alendronate treatment in osteoporotic patients affected by monoclonal Gammopathy of undetermined significance

In patients with monoclonal gammopathy of undetermined significance (MGUS) the increase of bone turnover rate can increase the risk of fracture. Thus, a treatment normalizing this negative balance could be of benefit in these patients. We studied 100 patients affected by MGUS, grouped according to the presence (group A, 50 patients) or absence (group B) of vertebral fractures and/or osteoporosis. Group A was treated with alendronate (70 mg/weekly) plus calcium and cholecalciferol for 18 months, and group B was treated with calcium and cholecalciferol. After 18 months, the mean bone mineral density (BMD) of the lumbar spine and total femur had increased by 6.1% and 1.5%, respectively, in group A. In the nine patients of this group not taking alendronate, BMD values of the lumbar spine and total femur decreased by 1.6% (P <= 0.001) and 1.3% (P <= 0.01), respectively. In patients of group B, BMD increased by 1.2% at the lumbar spine and decreased by 1.2% at the total femur. Corresponding figures of those patients in the same group not taking calcium and vitamin D supplementation were -0.1% and -1.2%, respectively. At 18 months we observed significant decreases of serum bone markers: the difference between the groups was -23.2 (P <= 0.01) for bone alkaline phosphatase, -23.6 for osteocalcin (P <= 0.01), -35.1 for C-terminal telopeptides of collagen type I (P <= 0.001), and -0.47 for bone sialoprotein (P = nonsignificant). Treatment with alendronate could lead to a significant reduction in fracture risk in MGUS patients with skeletal fragility

Lumbar bone mineral density as the major factor determining increased prevalence of vertebral fractures in monoclonal gammopathy of undetermined significance

The possible relationships between biochemical measurements and both densitometric and radiographic indexes of skeletal fragility were evaluated in 65 postmenopausal women with monoclonal gammopathy of undetermined significance (MGUS). There was a significantly higher prevalence of vertebral fractures in the MGUS group compared with a control population (P <= 0.001). The MGUS patients were then grouped according to the presence or absence of at least one mild vertebral fracture. Patients with fractures (Fx, n = 34) were older (62.8 +/- 6.1 years), with long-standing disease (8.8 +/- 7.1 years) when compared with those without fractures (NFx, n = 31; 59.7 +/- 5.0 years, P <= 0.05 and 5.8 +/- 4.1 years, P <= 0.05). The receptor activator of nuclear factor kappa-B ligand/osteoprotegerin ratio was higher in Fx compared with NFx (0.092 +/- 0.018 vs. 0.082 +/- 0.020; P <= 0.05). Lumbar spine (0.811 +/- 0.14 vs. 0.956 +/- 0.12 g/cm(2)), femoral neck (0.660 +/- 0.09 vs. 0.747 +/- 0.10 g/cm(2)) and total bone mineral density (BMD) (0.788 +/- 0.11 vs. 0.884 +/- 0.11 g/cm(2)) were lower (all P <= 0.001) in Fx-MGUS compared with Nfx patients. Receiver operating characteristic curves identified lumbar BMD as the variable that best predicted vertebral fractures (area under the curve 0.817; 95% confidence interval, 0.713-0.921). This study provides an indication for the measurement of BMD in MGUS patients, as a means of predicting vertebral fractures, especially in those that are asymptomatic. Patients with prevalent fractures should undergo pharmacological treatment to prevent further fractures

Effect of a single intravenous zoledronic acid administration on biomarkers of acute kidney injury (AKI) in patients with osteoporosis: a pilot study

The pilot study was designed to evaluate the early effect of intravenous (iv) zoledronic acid (ZA) on renal function. METHODS: Five mg iv ZA was administered to 23 patients with osteoporosis (17 women and 6 men, mean age 73±7 SD years). Urinary NGAL, KIM-1, and MCP-1, plasma (p) MCP-1 and serum (s) IL-18, serum calcium (sCa), Creatinine clearance (CrCl), parathyroid hormone (PTH), plasma C-terminal FGF23 (pFGF23), serum (s) Klotho, calcium excretion (CaEx) and renal threshold phosphate concentration/GFR (TmPO4/GFR) were assessed at baseline, 24 hours (h) and day (d) 30 after administration. RESULTS: There was a significant decrease in sCa and CaEx at 24 h (-4.1±2.8%, p<0.01 and -28±59%, p<0.05, respectively) and d 30 (-3.9±4%, p<0.001 and 26±43%, p<0.01) and a significant increase in PTH (79.8±95.8%) at d 30 (p<0.001) compared to baseline. TmPO4/GFR significantly decreased at 24 h and d 30 (-8.6±15.9%, p<0.05 and -11.3±13.5%, p<0.001) compared to baseline. We observed no difference in the concentration of pFGF23, sKlotho and urinary AKI biomarkers at any time occasions. Mean levels of sIL-18 and pMCP-1 significantly increased at 24 h (44±88%; p<0.01 and 198±237%; p<0.001) and returned to baseline at d 30. CONCLUSIONS: Our pilot study suggests that there is no direct acute effect of ZA on kidney function. The increase in plasma MCP-1 and serum IL-18 concentration could be associated with the stimulation of immunity mechanisms occurring soon after the administration of the drug. Secondary hyperparathyroidism develops shortly after the infusion of ZA and maintained even after one month

Factors affecting vitamin D deficiency in active inflammatory bowel diseases

Background: Hypovitaminosis D is prevalent in inflammatory bowel disease (IBD) and may be associated with disease activity. Aim: This study evaluated vitamin D (VitD) status in an Italian cohort of IBD patients, not taking VitD supplementation. We investigated risk factors for VitD deficiency and its correlation with disease activity. Methods: VitD levels were measured in 300 consecutive outpatients (42% with Crohn's Disease (CD) and 58% with ulcerative colitis (UC), 56% male) from a tertiary referral center. Data from the IBD cohort were compared with those of 234 healthy controls, matched by sex, age, and the month in which VitD levels were measured. Results: The mean VitD level in IBD patients was significantly lower than in controls (18.9 ng/ml vs. 25 ng/ml, p < 0.001) when accounting for gender, age, and season. VitD deficiency was present in 62% of IBD patients. Risk factors for deficiency were: age <40 and ≥60 years, winter, previous surgery, C-reactive protein (CRP) ≥0.5 mg/dl, and erythrocyte sedimentation rate ≥20 mm/h. In multivariate analysis, VitD levels were negatively influenced by disease location and CRP in UC. Conclusions: Although VitD deficiency was more prevalent than expected in healthy controls living in a Mediterranean country not at high risk of hypovitaminosis D, it was more common and severe in IBD patients. This study also found an association between VitD status and disease activit

Effects of free fatty acids on ACTH and cortisol secretion in anorexia nervosa

Objective: Free fatty acids (FFAs) exert a stimulatory effect on the hypothalamic–pituitary–adrenal (HPA) axis in animals and inhibit spontaneous ACTH and cortisol secretion in humans. Patients with anorexia nervosa display concomitant HPA axis hyperactivity and increased lipolysis. We studied the effects of a lipid load on ACTH and cortisol secretion in patients with anorexia nervosa in comparison with normal subjects. Design: Eight women with anorexia nervosa (ANW; means ± s.e.m.: 23.9 ± 2.3 years of age; body mass index (BMI): 14.9 ± 0.6 kg/m2) and seven normal women (NW; 25.6 ± 2.3 years of age; BMI: 22.8 ± 1.9 kg/m2) had FFA, ACTH, cortisol, glucose and insulin levels measured in the morning every 30 min for 180 min during i.v. saline or lipid-heparin emulsion (LHE) infusion. Results: During saline infusion, ACTH and cortisol levels decreased spontaneously in both groups, ACTH and cortisol levels in ANW being higher than in NW. LHE infusion led to increased FFA levels in both groups (P < 0.005). The ACTH and cortisol decrease in NW was more marked than during saline infusion (P < 0.05). LHE infusion in ANW was associated with a more pronounced decrease in ACTH levels than during saline infusion (P < 0.05), while cortisol levels were unchanged. At the end of the LHE infusion, a progressive decrease in FFA levels was associated with an increase in ACTH and cortisol concentrations in NW (P < 0.05) but not in ANW in whom FFA levels decreased to a lesser extent (P < 0.05). Conclusions: This study showed that corticotroph sensitivity to the inhibitory effect of an FFA load is preserved in patients with anorexia nervosa, in spite of persistent adrenal hyperactivity