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.

[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.

Value of multilocus genetic risk score for atrial fibrillation in end-stage kidney disease patients in a Polish population.

Genetic factors play a key role in the pathogenesis of atrial fibrillation (AF). We would like to establish an association between previously described single-nucleotide polymorphisms (SNPs) and AF in haemodialysed patients with end-stage kidney disease (ESKD-HD) as well as to assess the cumulative effect of all genotyped SNPs on AF risk. Sixteen SNPs were genotyped in 113 patients with AF-ESKD-HD and in 157 controls: without AF (NAF) and with ESKD-HD. The distribution of the risk alleles was compared in both groups and between different sub-phenotypes. The multilocus genetic risk score (GRS) was calculated to estimate the cumulative risk conferred by all SNPs. Several loci showed a trend toward an association with permanent AF (perm-AF): CAV1, Cx40 and PITX2. However, GRS was significantly higher in the AF and perm-AF groups, as compared to NAF. Three of the tested variables were independently associated with AF: male sex, history of myocardial infarction (MI) and GRS. The GRS, which combined 13 previously described SNPs, showed a significant and independent association with AF in a Polish population of patients with ESKD-HD and concomitant AF. Further studies on larger groups of patients are needed to confirm the associations.

Brivaracetam disposition in renal impairment.

Brivaracetam is a novel high-affinity SV2A ligand currently in clinical development for epilepsy. The objective was to characterize its disposition in patients with renal impairment. A single oral dose of 200 mg brivaracetam was administered to 9 patients with severe renal impairment not requiring dialysis (creatinine clearance <15 mL/min, n = 6; 15-29 mL/min, n = 3) and 9 matched healthy controls. Plasma and urinary concentrations of brivaracetam and 3 pharmacologically inactive metabolites (acid, hydroxy, and hydroxyacid) were determined up to 72 hours postdose, and noncompartmental pharmacokinetic parameters were derived. The C(max) of brivaracetam was unchanged relative to healthy controls, whereas AUC was slightly increased (mean ratio, 1.21; 90% confidence interval, 1.01-1.45). Nonrenal and renal clearances of brivaracetam decreased from 47 and 4.5 to 41 and 1.7 mL/min/1.73 m(2). Exposure to the acid, hydroxy, and hydroxyacid metabolites was markedly increased: C(max) by 2.4-, 2.0-, and 11.7-fold and AUC by 3.2-, 4.1-, and 21.5-fold. Renal clearance of these rapidly cleared metabolites was decreased 10-fold in patients with severe renal impairment. Nonclinical toxicology studies concluded to the absence of safety issues related to the increased levels of metabolites. These observations suggest that dose adjustment of brivaracetam should not be required at any stage of renal dysfunction.

Translumbar inferior vena cava cannulation.

BACKGROUND: The aim of the study was to review our three year experience with translumbar insertion of dialysis catheters. METHODS: In five adult patients (4 males and one female, mean age 45 yr), requiring dialysis due to end-stage chronic renal failure, the inferior vena cava was cannulated because of the impossibility of using any other approach. All procedures were performed under fluoroscopy. After visualisation of the inferior vena cava by injection of contrast medium into a peripheral vein, the vena cava was punctured with a 20 cm long needle, at the L3 level. The position of the needle was confirmed by injection of contrast medium, and the vein was then cannulated with a peel-away cannula, using a standard Seldinger technique. Subsequently, a pre-tunneled silastic catheter was introduced and secured. RESULTS: The catheters were used for from 3 to 10 months. No case of permanent catheter dysfunction was noted. Three episodes of temporary thrombosis, in two patients, were successfully treated with heparin and urokinase. Three catheters became contaminated, but they were treated without the necessity for catheter removal. CONCLUSION: The described method is a safe and effective way of securing haemodialysis access in patients where a standard approach is not possible.

Endometrial morphology and pituitary-gonadal axis dysfunction in women of reproductive age undergoing chronic haemodialysis--a multicentre study.

BACKGROUND: Although disorders of the reproductive system are very common in women undergoing chronic haemodialysis, this issue remains a neglected area. The aim of the study was to evaluate the endometrial morphology and its relationship with pituitary-gonadal axis dysfunction in uraemic women of reproductive age undergoing haemodialysis. METHODS: The baseline survey with determination of the sex hormones concentrations was performed in 75 haemodialysed women aged 18-45 years. The control group consisted of 33 healthy premenopausal women, aged 18-45 years, with normal menstruation. Then, 40 haemodialysis women, who met the inclusion criteria and gave their informed consent, underwent endometrium suction biopsy. RESULTS: The pathological endometrial morphology was observed in 80% of biopsied subjects. Atrophia or subatrophia was recognized in almost half of the cases, and proliferative changes in one-third of them. Full atrophia with no mitotic figures was found in all but one non-menstruating woman. In one case, adenocarcinoma in situ was diagnosed and successfully treated. The analysis of the relationship between hormonal status and endometrial morphology revealed the substantial influence of oestradiol on endometrium as a target organ. In women with atrophic changes, oestradiol concentrations were significantly decreased, whereas in the remaining subjects, the increase of serum oestradiol seemed to be accompanied by a shift in endometrium morphology from secretional pattern, through proliferative changes to glandular hyperplasia. Mean serum 17-beta oestradiol was decreased in women with amenorrhoea, and increased in those with eumenorrhoea (P<0.001). Except women with regular menses, mean serum progesterone concentrations were in the lower normal range. Seventy-five percent of the studied population had menstrual disorders, and amenorrhoea constituted almost a half of them. CONCLUSIONS: Pathological endometrium morphology is very common in uraemic women of reproductive age undergoing haemodialysis, with proliferative changes in one-third and atrophia in almost a quarter of them. The results of the study suggest a preserved normal reactivity of endometrium on circulating oestrogens.

[Menstrual disturbances and alternations in hypophyseal gonadal axis in end-stage premenopausal women undergoing hemodialysis: a multi-center study]. / Zaburzenia miesiaczkowania i osi przysadkowo-gonadalnej u kobiet w wieku rozrodczym hemodializowanych z powodu schylkowej niewydolnosci nerek--badanie wieloosrodkowe.

The results of the studies of hypophyseal-gonadal axis in dialysis women are not uniform. Mostly the increased serum concentrations of prolactine and pituitary gonadotropins are observed; the data about ovarian secretion are much more scanty and contradictory. The aim of this crossectional study was to assess changes in sexual hormones secretion and their associations with menstrual disturbations in premenopausal women with end-stage renal failure undergoing hemodialysis. Sixty three women from six mazovian dialysis units, aged 18-45 years (mean 35 +/- 7 years) were enrolled into the study. They were divided into four groups according to their menstrual pattern: I--eumenorrhoea (n = 17), II--polymenorrhoea (n = 9), III--oligomenorrhoea (n = 16) i IV--amenorrhoea n = 21). There were no differences between both groups in respect to age, age of menarche, time on hemodialysis, and body mass index. In all subjects gynecological examination was performed and serum prolactin, FSH, LH, estradiol, progesterone and testosterone concentrations were assayed. In 49% women high serum prolactin concentrations were noted (the highest in group IV--1699 +/- 1022 vs 441 +/- 205 microIU/ml in group I; p < 0.05). Mean serum FSH and LH were increased in group IV only (33 +/- 59 and 22 +/- 31 mIU/ml); no significant differences among groups examined were seen. Serum estradiol was increased in groups I-III (95 +/- 46, 72 +/- 33, and 83 +/- 55 pg/ml, respectively) and decreased in group IV (27 +/- 22 pg/ml; p < 0.001 in respect to remaining groups). Mean serum progesterone and testosterone concentrations were normal in all four groups, but serum progesterone was significantly lower in groups II-IV than in group I (p < 0.05). No differences in hormonal status between patients receiving and not receiving rHuEpo were observed. Menstrual disturbances are common (73%) in premenopausal women with end-stage renal failure, with amenorrhea constituting a half of them. Hyperprolactinemia is the most frequently seen alteration in their hormonal profile with the highest concentrations in those with secondary amenorrhea. Increased serum gonadotropins and reduced serum estradiol concentrations are mostly seen in amenorrheic women, whereas in menstruating women serum estradiol is often slightly increased.