[Circulating bone turnover markers and their relationships in hemodialysis patients with vitamin D deficiency].

OBJECTIVE: Introduction: Mineral homeostasis is achieved through a complex interplay of several feedback processes involving primarily the bone, intestine and kidney, regulated by different proteins acting on endocrine, paracrine or autocrine levels. The dysregulation of these processes in chronic renal failure, called kidney disease (CKD) - mineral and bone disorder (CKD-MBD), although apparent, is still poorly understood. The aim: The aim of the study was an analysis of potential relationships between selected biomarkers of CKD-MBD in maintenance hemodialysis (HD) patients. PATIENTS AND METHODS: Material and Methods: In the first part of this cross-sectional study, the 25(OH)D serum concentrations were measured in 115 HD vitamin D naïve patients from 5 dialysis units located in central Poland. Thereafter in 81 patients (49 men, 32 women, aged 67 ± 13 years) with vitamin deficiency (25(OH)D <20 ng/ml) serum concentrations of 25(OH)D, 1,25(OH)2D, intact parathyroid hormone (iPTH), intact FGF23, sclerostin (SCL), osteocalcin (OC), and C-terminal telopeptide of type I collagen (CTX1) were determined. RESULTS: Results: Serum levels of both 25(OH)D and 1,25(OH)2D were low (mean values 13.4±6.72 ng/ml and 12.9 ± 9.08 pmol/l, respectively). While serum 25(OH)D correlated only with a declared time spent outside (r= 0.411; p=0.000139), serum 1,25(OH)2D was related to diuresis (r= 0.289; p=0.009), and negatively to time on dialysis (r= -0.272; p=0.014) , serum phosphate (r= -0.393; p=0.000289), FGF23(r= -0.295; p=0.008), and SCL (r= -0.260; p=0.019). There was a marked dispersion of FGF-23 serum levels across the group (mean 823±5647, median 379 pg/ml) , and - as expected - they correlated highly with phosphate (r= 0.549, p=0.000), calcium (r= 0,328, p=0,003), OC (r=0.479; p=0.000), and negatively with z 1,25(OH)2D (r= -0.295, p=0.008). Mean serum SCL levels (89.2±46.7, median 81.9 pmol/l) were 3x higher than in general population, and correlated highly positively with dialysis vintage (r=0.402; p<0.001), age (r=0.356; p=0.001), as well as negatively with 1,25(OH)2D (r= -0.260; p=0.019) and CTX1 (r= -0.293; p=0.008). CONCLUSION: Conclusions: In our hemodialysis population, in addition to profoundly impaired 1,25(OH)2D synthesis, there is also a widespread prevalence of 25(OH)D deficiency. The patients have also markedly increased serum bone-secreted proteins, FGF23, and SCL, which regulate mineral and bone metabolism and are associated with the systemic side effects of uremia. All these hormones interact one with the other, creating a sophisticated cross-talk between the bone, intestine, and the kidney.

Cholecalciferol vs. Small Doses of Alfacalcidol vs. Placebo in Chronic Kidney Disease Patients on Hemodialysis: A Randomized Parallel Group Study.

BACKGROUND: The ability of extrarenal tissues to convert 25(OH)D (calcidiol) into 1,25(OH)2D (calcitriol) and dependence of the conversion on substrate levels provide the rationale for supplementing vitamin D in dialysis patients who usually have severe depletion of both: 25(OH)D and 1,25(OH)2D. The primary aim of the study was to compare effects of small doses of cholecalciferol (12,000 IU/week) with frequently used in Europe, small doses of alfacalcidol (1.5 µg/week) or placebo, given for 12 weeks, on serum 1,25(OH)2D in hemodialysis patients with 25(OH)D deficiency. Secondary outcomes were changes in serum calcium, phosphate, 25(OH)D, parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23) and sclerostin during the treatment. METHODS: This was a prospective, randomized, partly double-blind (cholecalciferol vs. placebo) study. Out of 522 patients dialyzed in 5 centers in the Mazovian Province, 93 gave informed consent and met the inclusion criteria: any vitamin D metabolites and calcimimetics naïve; no history of liver or intestinal disease; serum 25(OH)D <20 ng/ml, iPTH <1,000 ->110 pg/ml, calcium <10.2, and phosphate <6.8 mg/dl. The subjects were stratified by serum iPTH, then randomized into 3 groups according to the treatment. RESULTS: To our knowledge, this is the first study comparing head-to-head these drugs in the hemodialysis population. There were no significant differences between the groups at baseline. 81 patients completed the study. Cholecalciferol normalized serum 25(OH)D, with a mean rise from 12.9 ± 6.7 to 31.3 ± 10.1 ng/ml (p < 0.0001). This was accompanied by a marked increase of 1,25(OH)2D from 13.8 ± 9.3 to 25.1 ± 14.2 pmol/l (p < 0.0001). A rise in serum 1,25(OH)2D was also observed in alfacalcidol treated patients, however much smaller (from 13.5 ± 10.1 to 18.5 ± 11.0 pmol/l; p = 0.02). Neither cholecalciferol nor alfacalcidol treatment resulted in significant changes in serum PTH and the remaining parameters. CONCLUSIONS: In most patients, treatment with cholecalciferol in a 12,000 IU/week dose permits safe correction of 25(OH)D deficiency and is more effective than 1.5 µg/week dose of alfacalcidol in rising serum 1,25(OH)2D. This, together with a lack of influence on circulating iPTH the usefulness of such small alfacalcidol doses in hemodialysis patients is debatable.

FRAX prognostic and intervention thresholds in the management of major bone fractures in hemodialysis patients: A two-year prospective multicenter cohort study.

PURPOSE: The usefulness of FRAX in predicting major bone fractures in patients with end-stage kidney disease on maintenance hemodialysis treatment has been confirmed in previous studies. For meaningful clinical use, the prognostic and intervention FRAX thresholds need to be established. METHODS: The primary aim of our study was to calculate the optimal cut-off point of FRAX for the best prediction of an increased bone fracture risk in dialysis patients and additionally, to propose its intervention threshold, indicating the need for antifracture pharmacological treatment. The study included 718 hemodialysis patients, who were followed up for two years. Thirty low-energy major bone fractures were diagnosed during the study period. We used the Polish version of FRAX (without the DXA examination) and some particular variables of the FRAX calculator. The optimal cut-off point for prediction of an increased major bone fracture risk was based on the analysis of the sensitivity and specificity curves of FRAX. RESULTS: The analysis revealed FRAX >5% (sensitivity of 70.0%, specificity of 69.8%) as the prognostic threshold for major bone fractures. Its sensitivity for bone fracture prediction was significantly higher, but specificity lower than those of FRAX ≥10%, used in general Polish population. The reason for this can be an underestimation of bone fracture risk with FRAX in dialysis patients. CONCLUSIONS: We conclude that the FRAX prognostic threshold for identification of an increased risk of major bone fractures in hemodialysis patients is >5%. We propose to use this specific value of FRAX as an intervention threshold for pharmacological antifracture treatment in hemodialysis patients.

Factors associated with irritable bowel syndrome symptoms in hemodialysis patients.

AIM: To investigate clinical characteristics associated with the presence of irritable bowel syndrome (IBS) symptoms in hemodialysis (HD) patients. METHODS: This was a cross-sectional study. A questionnaire based on the Bowel Disease Questionnaire that records gastrointestinal symptoms was given to 294 patients in 4 dialysis centers. A total of 196 (67%) subjects returned the survey. A multivariable logistic regression model was used to identify factors significantly associated with IBS symptoms. RESULTS: Symptoms compatible with IBS were present in 27 (13.8%) subjects and independently associated with low post-dialysis serum potassium [OR = 0.258, 95% CI (0.075-0.891), P = 0.032], paracetamol use [OR = 3.159, 95% CI (1.214-8.220), P = 0.018], and Kidney Disease Quality of Life (KDQOL) cognitive function score [OR = 0.977, 95% CI (0.956-0.999), P = 0.042]. Univariate regressions were also performed and the reported significance is for multivariate analysis. No association was detected for age, gender, depressed mood, smoking (present or past), body mass index, albumin level, Kt/V, sodium pre- or post-dialysis level, change in potassium level during HD, proton pump inhibitor or H2 blocker use, aspirin use, residual diuresis, hepatitis B or C infection, diabetes mellitus, marital status and education level. CONCLUSION: This study examined potential risk factors for symptoms compatible with IBS in HD patients and identified an association with paracetamol use, post-dialysis potassium level and KDQOL-cognitive function score.