Effects of vitamin D supplementation on FGF23: a randomized-controlled trial.

PURPOSE: Fibroblast growth factor-23 (FGF23) is critical for phosphate homeostasis. Considering the high prevalence of vitamin D deficiency and the association of FGF23 with adverse outcomes, we investigated effects of vitamin D3 supplementation on FGF23 concentrations. METHODS: This is a post-hoc analysis of the Styrian Vitamin D Hypertension trial, a single-center, double-blind, randomized, placebo-controlled trial, conducted from 2011 to 2014 at the Medical University of Graz, Austria. Two hundred subjects with 25(OH)D concentrations < 30 ng/mL and arterial hypertension were randomized to receive either 2800 IU of vitamin D3 daily or placebo over 8 weeks. Primary outcome was the between-group difference in FGF23 levels at study end while adjusting for baseline values. RESULTS: Overall, 181 participants (mean ± standard deviation age, 60.1 ± 11.3; 48% women) with available c-term FGF23 concentrations were considered for the present analysis. Mean treatment duration was 54 ± 10 days in the vitamin D3 group and 54 ± 9 days in the placebo group. At baseline, FGF23 was significantly correlated with serum phosphate (r = 0.135; p = 0.002). Vitamin D3 supplementation had no significant effect on FGF23 in the entire cohort (mean treatment effect 0.374 pmol/L; 95% confidence interval - 0.024 to 0.772 pmol/L; p = 0.065), but increased FGF23 concentrations in subgroups with baseline 25(OH)D concentrations below 20 ng/mL (n = 70; mean treatment effect 0.973 pmol/L; 95% confidence interval - 0.032 to 1.979 pmol/L; p = 0.019) and 16 ng/mL (n = 40; mean treatment effect 0.593 pmol/L; 95% confidence interval 0.076 to 1.109; p = 0.022). CONCLUSIONS: Vitamin D3 supplementation had no significant effect on FGF23 in the entire study cohort. We did, however, observe an increase of FGF23 concentrations in subgroups with low baseline 25(OH)D.

Vitamin D status and mortality in chronic kidney disease.

BACKGROUND: Vitamin D deficiency is found in the majority of patients with chronic kidney disease (CKD) and may contribute to various chronic diseases. Current guidelines suggest correcting reduced 25-hydroxyvitamin D [25(OH)D] concentrations in CKD patients with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2). Whether low 25(OH)D levels in these patients are associated with higher mortality is unclear. This issue was addressed in the present work. METHODS: We examined 444 patients with eGFR <60 mL/min/1.73 m(2) from the Ludwigshafen Risk and Cardiovascular Health Study. This prospective cohort study includes Caucasian patients without primary kidney disease who were routinely referred to coronary angiography at baseline (1997-2000). RESULTS: During a median follow-up time of 9.4 years, 227 patients died including 159 deaths from cardiovascular causes. Multivariate adjusted hazard ratios (HRs) (with 95% confidence intervals) in severely vitamin D-deficient [25(OH)D <10 ng/mL] compared to vitamin D-sufficient patients [25(OH)D ≥ 30 ng/mL] were 3.79 (1.71-8.43) for all-cause and 5.61 (1.89-16.6) for cardiovascular mortality. Adjusted HRs per 10 ng/mL increase in 25(OH)D levels were 0.63 (0.50-0.79) for all-cause and 0.59 (0.45-0.79) for cardiovascular mortality. There was no significant interaction with parathyroid hormone concentrations. CONCLUSIONS: Low 25(OH)D levels are associated with increased all-cause and cardiovascular mortality in CKD patients. These findings support suggestions to correct vitamin D deficiency, but whether vitamin D supplementation improves survival remains to be proven in randomized controlled trials.

Estimation versus measurement of the glomerular filtration rate for kidney function assessment in patients with cancer undergoing cisplatin-based chemotherapy.

Glomerular filtration rate (GFR) assessment is indicated before every administration of cisplatin. The optimal modality for this purpose [GFR measurement by urinary Creatinine Clearance (uCrCl) versus GFR estimation (eGFR) by the CKD-EPI formula versus both] is unclear. We investigated whether eGFR only is safe in this setting. Paired uCrCl and eGFR determinations from 470 cisplatin cycles from 121 patients were analyzed [median age: 55 years; most frequent tumor site: genitourinary (45%); palliative treatment: n = 41 (34%)]. Primary endpoint was the proportion of cycles with uCrCl < 50 ml/min/1.73m2 and eGFR ≥ 50 ml/min/1.73m2 (i.e. a "false negative" result when only determining eGFR). The primary endpoint occurred in 8 of 470 cisplatin cycles (1.7%, 95%CI 0.5-2.9). In all 8 events, uCrCl was lower than eGFR (mean uCrCl vs. eGFR: 43 versus 112 ml/min/1.73m2). The uCrCl was re-measured in all patients, and showed normal results in all but 1 patient. None of these events precluded the administration of cisplatin at the planned date, and no subsequent cases of acute nephrotoxicity occurred. Overall agreement between uCrCl and eGFR was low, with qualitative analysis suggesting frequent incompliance with 24-h urine collection. We conclude that an eGFR is sufficient for assessing kidney function in patients with cancer undergoing cisplatin therapy.

Role of etelcalcetide in the management of secondary hyperparathyroidism in hemodialysis patients: a review on current data and place in therapy.

Secondary hyperparathyroidism (sHPT) is a frequently occurring severe complication of advanced kidney disease. Its clinical consequences include extraskeletal vascular and valvular calcifications, changes in bone metabolism resulting in renal osteodystrophy, and an increased risk of cardiovascular morbidity and mortality. Calcimimetics are a cornerstone of parathyroid hormone (PTH)-lowering therapy, as confirmed by the recently updated 2017 Kidney Disease: Improving Global Outcomes chronic kidney disease - mineral and bone disorder clinical practice guidelines. Contrary to calcitriol or other vitamin D-receptor activators, calcimimetics reduce PTH without increasing serum-calcium, phosphorus, or FGF23 levels. Etelcalcetide is a new second-generation calcimimetic that has been approved for the treatment of sHPT in adult hemodialysis patients. Whereas the first-generation calcimimetic cinacalcet is taken orally once daily, etelcalcetide is given intravenously thrice weekly at the end of the hemodialysis session. Apart from improving drug adherence, etelcalcetide has proven to be more effective in lowering PTH when compared to cinacalcet, with an acceptable and comparable safety profile. The hope for better gastrointestinal tolerance with intravenous administration did not come true, as etelcalcetide did not significantly mitigate the adverse gastrointestinal effects associated with cinacalcet. Enhanced adherence and strong reductions in PTH, phosphorus, and FGF23 could set the stage for a future large randomized controlled trial to demonstrate that improved biochemical control of mineral metabolism with etelcalcetide in hemodialysis patients translates into cardiovascular and survival benefits and better health-related quality of life.

Visceral leishmaniasis in a patient with diabetes mellitus type 2 and discrete bicytopenia.

An Austrian patient with diabetes mellitus type 2 developed visceral leishmaniasis after trips to Spain and Crete, presenting with slight bicytopenia, later developing severe pancytopenia. Travel history taking is important due to an extended incubation period. Coexistence of diabetes mellitus can impair T lymphocyte function and cause higher relapse rates.

Vitamin D prohormone in the treatment of secondary hyperparathyroidism in patients with chronic kidney disease.

Secondary hyperparathyroidism (sHPT) represents the adaptive and very often, finally, maladaptive response of the organism to control the disturbed homeostasis of calcium, phosphorus, and vitamin D metabolism caused by declining renal function in chronic kidney disease (CKD). sHPT leads to cardiovascular and extravascular calcifications and is directly linked to an increased risk of cardiovascular morbidity and mortality as well as excess all-cause mortality. Vitamin D plays an important role in the development of sHPT. CKD patients are characterized by a high prevalence of hypovitaminosis D. Supplementation with both vitamin D prohormones cholecalciferol and ergocalciferol enables the achievement and maintenance of a normal vitamin D status when given in adequate doses over an appropriate treatment period. In patients with earlier stages of CKD, sHPT is influenced by and can be successfully treated with vitamin D prohormone supplementation, whereas in patients with very late stages of CKD and those requiring dialysis, treatment with prohormones seems to be of limited efficacy. This review gives an overview of the pathogenesis of sHPT, summarizes vitamin D metabolism, and discusses the existing literature regarding the role of vitamin D prohormone in the treatment of sHPT in patients with CKD.

Mortality in dialysis patients with cinacalcet use: A large observational registry study.

BACKGROUND: Secondary hyperparathyroidism (sHPT) is associated with higher mortality in dialysis patients. The calcimimetic cinacalcet reduces intact parathyroid hormone (iPTH) in dialysis patients. The randomized controlled EVOLVE trial failed to unequivocally prove survival advantage of cinacalcet in dialysis patients. However, recent post hoc analyses suggested a benefit in subgroups of dialysis patients. Large observational cohort studies may represent an option to better determine such subgroups. METHODS: Data from the nationwide Austrian registry of dialysis patients between January 2004 and December 2009 were analyzed with follow-up until December 2010. All-cause and cardiovascular mortality analyses were performed using the Kaplan-Meier and Cox proportional hazards regression. To reduce confounding effects a propensity score (PS) based method (matching by stratification) was used for group comparison. RESULTS: The cohort included 7983 dialysis patients, 1572 (19.7%) were prescribed cinacalcet. During a median follow-up of 2.7years, 3574 (44.8%) patients died, including 1342 (16.8%) deaths from cardiovascular causes. Survival analyses in the PS-matched study population (n=6109) showed lower all-cause mortality for cinacalcet-treated as compared to untreated patients only in subsets characterized by younger age, low prevalence of diabetes, iPTH levels between 300 and 599pg/mL, concomitant therapy with vitamin D and phosphate binders. CONCLUSIONS: Our data suggest that a subgroup of dialysis patients, namely those with moderate sHPT, younger age and without diabetes benefit from cinacalcet with reduced overall and cardiovascular mortality. These findings may help to identify populations for further controlled trials and may allow a more individualized sHPT treatment using cinacalcet in specific patient subgroups.

Response to active hepatitis B vaccination and mortality in incident dialysis patients.

All patients with advanced chronic kidney disease or on renal replacement therapy should receive active hepatitis B vaccination. The aim of this retrospective cohort study was to investigate the association between the immune response to hepatitis B vaccination and all-cause, cardiovascular or infection-related mortality in incident dialysis patients starting dialysis between 2001 and 2008 (n=426) in two Austrian dialysis centers. Vaccination response was defined as follows: absent anti-HBs antibody titer or a titer <10IU/L was classified as non-response, seroconversion (SC) was defined as a titer ⩾10IU/L, and seroprotection (SP) as a titer ⩾100IU/L. Kaplan-Meier survival curves and multivariable adjusted Cox Proportional Hazards Models were used to determine the association between vaccination response and all-cause, cardiovascular and infection-related mortality. Of all patients 207 (48.6%) were non-responders, SC was observed in 219 (51.4%), SP in 118 (27.7%) patients. During a median follow-up of 51.2 months 228 (53.5%) patients died. Patients with SP and SC showed a significantly lower all-cause (p<0.001 for both) and cardiovascular mortality (p=0.006 for SP, p=0.01 for SC). SP and SC were independently associated with a significant risk reduction for all-cause mortality (SP: HR 0.69, 95% CI 0.49-0.97, p=0.03; SC: HR 0.72, 95% CI 0.55-0.95, p=0.02). In conclusion, achieving seroconversion and seroprotection after active hepatitis B vaccination is associated with significantly reduced all-cause mortality in incident dialysis patients. This simple and readily available tool allows estimation of patient survival independently of other well-known key parameters such as age, gender, the presence of diabetes and markers of malnutrition and inflammation.

Effects of Vitamin D Supplementation on Bone Turnover Markers: A Randomized Controlled Trial.

Bone turnover markers (BTMs) are used to evaluate bone health together with bone mineral density and fracture assessment. Vitamin D supplementation is widely used to prevent and treat musculoskeletal diseases but existing data on vitamin D effects on markers of bone resorption and formation are inconsistent. We therefore examined the effects of vitamin D supplementation on bone-specific alkaline phosphatase (bALP), osteocalcin (OC), C-terminal telopeptide (CTX), and procollagen type 1 N-terminal propeptide (P1NP). This is a post-hoc analysis of the Styrian Vitamin D Hypertension Trial, a single-center, double-blind, randomized, placebo-controlled trial (RCT) performed at the Medical University of Graz, Austria (2011-2014). Two hundred individuals with arterial hypertension and 25-hydroxyvitamin D (25[OH]D) levels <75 nmol/L were randomized to 2800 IU of vitamin D daily or placebo for eight weeks. One hundred ninety-seven participants (60.2 ± 11.1 years; 47% women) were included in this analysis. Vitamin D had no significant effect on bALP (mean treatment effect (MTE) 0.013, 95% CI -0.029 to 0.056 µg/L; p = 0.533), CTX (MTE 0.024, 95% CI -0.163 to 0.210 ng/mL, p = 0.802), OC (MTE 0.020, 95% CI -0.062 to 0.103 ng/mL, p = 0.626), or P1NP (MTE -0.021, 95% CI -0.099 to 0.057 ng/mL, p = 0.597). Analyzing patients with 25(OH)D levels <50 nmol/L separately (n = 74) left results largely unchanged. In hypertensive patients with low 25(OH)D levels, we observed no significant effect of vitamin D supplementation for eight weeks on BTMs.

Effects of Vitamin D Supplementation on IGF-1 and Calcitriol: A Randomized-Controlled Trial.

Increasing evidence suggests a possible interaction between vitamin D and insulin-like growth factor-1 (IGF-1). We aimed to investigate effects of vitamin D supplementation on IGF-1 (primary outcome) and calcitriol (1,25(OH)2D) concentrations (secondary outcome). This is a post-hoc analysis of the Styrian Vitamin D Hypertension Trial-a single-center, double-blind, randomized, placebo-controlled trial (RCT) conducted from 2011 to 2014 at the Medical University of Graz, Austria. Two-hundred subjects with arterial hypertension and 25(OH)D concentrations <30 ng/mL were randomized to either receive 2800 IU of vitamin D daily or placebo for eight weeks. A total of 175 participants (mean ± standard deviation age, 60 ± 11 years; 49% women) with available IGF-1 concentrations were included in the present analysis. At baseline, IGF-1 concentrations were significantly correlated with 1,25(OH)2D (r = 0.21; p = 0.005) but not with 25(OH)D (r = -0.008; p = 0.91). In the RCT, vitamin D had no significant effect on IGF-1 (mean treatment effect 3.1; 95% confidence interval -5.6 to 11.9 ng/mL; p = 0.48), but it increased 1,25(OH)2D concentrations (mean treatment effect 9.2; 95% confidence interval 4.4 to 13.9 pg/mL; p ≤ 0.001). In this RCT, in hypertensive patients with low 25(OH)D concentrations, there was no significant effect of vitamin D supplementation on IGF-1 concentrations. However, we observed a cross-sectional correlation between 1,25(OH)2D and IGF-1 and an increase of 1,25(OH)2D after vitamin D supplementation.

Awareness of chronic kidney disease in Austria: a frequently under-recognized clinical picture.

BACKGROUND: The prevalence of chronic kidney disease (CKD) is rising at an alarming rate, thus presenting a substantial burden for the patient as an individual and-because of the enormous treatment costs-for society as a whole. Early diagnosis and therapy could slow disease progression and reduce the prevalence of cost-intensive end stage renal disease. The aim of this study was to determine the accuracy of diagnosis of CKD in acute patients presenting at an internal ward. METHODS: Routine laboratory parameters of kidney function of 238 inpatients were retrospectively evaluated to determine the prevalence of CKD, defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m(2). Those results were compared with the actual documentation of the ICD-10 diagnosis CKD in the discharge reports of the respective patients. RESULTS: Of 238 patients, 228 patients were included in the analysis. The overall median (range) eGFR was 60.7 (10.4-171.9) mL/min/1.73 m(2), with no gender-specific difference. Of patients, 49.6 % (n = 113) were retrospectively diagnosed with CKD stage 3 or higher. However, the review of the discharge reports found correct diagnosis of CKD in only 38.1 % (n = 43) of these patients. CONCLUSIONS: The present analysis shows that CKD remains frequently unrecognized, even in a hospital setting. This could have dramatic implications on the care, treatment and prevention of CKD and associated complications.

Osteoporosis, weight gain and atypical fat accumulations - a typical feature not only for Cushing's, but also Madelung's disease: A case report.

Madelung's disease, or multiple symmetric lipomatosis, is an extremely rare disease and very likely to be under-diagnosed. It is characterized by multiple symmetrical non-encapsulated fat accumulations mainly located around the neck, shoulders, upper extremities and upper parts of the trunk. The disorder predominantly affects middle-aged men of Mediterranean origin with a history of ethanol intake. Reports of this uncommon disorder in women are very rare. The aim of this article is to report the endocrine and metabolic workup leading to the diagnosis of this uncommon disorder. A 55-year-old woman with osteoporosis was referred to our outpatient clinic with a suspected diagnosis of Cushing's disease. The patient complained of undesired weight gain with atypical fat accumulations predominantly in the upper trunk region during the previous 10 weeks. She presented with the characteristic physical features of Madelung's disease and underwent a thorough examination with endocrine and metabolic evaluation of this rare condition and was finally diagnosed with Madelung's disease. This report demonstrates how a diagnosis of this rare disorder can be reached efficiently. A history of osteoporosis in combination with weight gain and atypical fat accumulations ultimately led to the diagnosis of Madelung's diseases, a rather unknown disorder likely to be under-diagnosed. Although treatment options are limited, a diagnosis is still important for the affected individual.

Low 25-hydroxyvitamin D is associated with increased mortality in female nursing home residents.

CONTEXT: Vitamin D deficiency contributes to skeletal diseases and is highly prevalent among institutionalized elderly patients. Whether low 25-hydroxyvitamin D (25[OH]D) concentrations are an independent risk factor for mortality in these patients is, however, unclear. OBJECTIVE: We aimed to evaluate whether 25(OH)D concentrations are associated with mortality. DESIGN, SETTING, AND PARTICIPANTS: This is a prospective cohort study among elderly female patients (age >70 yr) recruited from 95 nursing homes in Austria. MAIN OUTCOME MEASURES: We calculated Cox proportional hazard ratios (HR) for all-cause mortality according to 25(OH)D quartiles. RESULTS: We examined 961 study participants (age 83.7 ± 6.1 yr). Median 25(OH)D concentration was 17.5 (interquartile range 13.7-25.5) nmol/liter, and 93% of our cohort had 25(OH)D levels below 50 nmol/liter. During a mean follow-up time of 27 ± 8 months, 284 patients died. Compared with the fourth quartile (25[OH]D >25.5 nmol/liter), the age-adjusted HR (with 95% confidence interval) was 1.49 (1.07-2.10) in the first 25(OH)D quartile (25[OH]D <14.0 nmol/liter), and this association remained significant after multivariate adjustments (HR = 1.56; 95% confidence interval = 1.01-2.40). CONCLUSIONS: This Austrian study suggests that the majority of institutionalized female patients are vitamin D deficient during winter and that there was an inverse association of 25(OH)D and mortality. These data underscore the urgent need for effective strategies for the prevention and treatment of vitamin D deficiency, in particular in the setting of nursing homes.

Vitamin D deficiency following Billroth II surgery - How much vitamin D is enough?: a case report.

BACKGROUND: Vitamin D deficiency with all its consequences is a global health problem. CASE PRESENTATION: We reported a 62-year-old Caucasian woman with alcohol-related liver cirrhosis (Child class A) and a medical history of Billroth II surgery. Although she has taken an oral dose of 16 800 IU vitamin D daily for six weeks to normalise her 25-hydroxyvitamin D level the raise was only moderate. CONCLUSION: High-dose oral or parenteral vitamin D therapy is necessary to gain sufficient 25-hydroxyvitamin D serum levels in patients following gastric surgery.

Structural elucidation of zwitterionic carbohydrates derived from glycosphingolipids of the porcine parasitic nematode Ascaris suum.

Carbohydrates substituted with phosphocholine (PC) and phosphoethanolamine (PE) were released from zwitterionic glycosphingolipids of the pig parasitic nematode Ascaris suum by treatment with endoglycoceramidase. Individual glycans were obtained by HPLC on porous graphitic carbon followed by high-pH anion-exchange chromatography. In addition to the known pentasaccharides Gal alpha 3GalNAc beta 4[PC6]GlcNAc beta 3Man beta 4Glc and Gal alpha 3GalNAc beta 4[PC6]GlcNAc beta 3[PE6]Man beta 4Glc, the corresponding tri- and tetra-saccharides, as well as components with elongated structures, could be identified by matrix-assisted laser-desorption ionization-time-of-flight MS, methylation analysis, 1H- and 13C-NMR spectroscopy, exoglycosidase cleavage and electrospray ionization ion-trap MS. The extended components comprised novel structural motifs such as di-substituted alpha-galactose carrying two beta-linked galactosyl residues, which were found to bear, in part, further fucose, galactose, N -acetylgalactosamine and/or N -acetylglucosamine moieties. Furthermore, additional fucosylation of the PC-substituted N -acetylglucosamine and a non-terminal fucosyl motif were detected. In conclusion, this study contributes significant new information on the glycome of nematodes.