Claudia Friedl

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.

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.

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.

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.

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

ZusammenfassungDie Madelung-Krankheit, auch bekannt als multiple symmetrische Lipomatose, ist eine sehr seltene Erkrankung und aufgrund dessen wird sie häufig nicht als solche diagnostiziert. Die Krankheit ist charakterisiert durch multiple symmetrische unkapsulierte Fettgewebsvermehrung mit Hauptlokalisation im Hals-Nackenbereich, der Schulterpartie, der oberen Extremitäten und im oberen Thoraxbereich. Die Madelung-Krankheit tritt vor allem bei Männern mittleren Alters mediterranen Ursprungs auf und ist zumeist mit einem Alkoholabusus assoziiert. Berichte dieser ungewöhnlichen Erkrankung bei Frauen sind selten. Ziel der Arbeit ist die diagnostische Aufarbeitung dieser seltenen Krankheit anhand eines Fallberichtes zu präsentieren. Eine 55-jährige Patientin mit Osteoporose wurde mit der Verdachtsdiagnose Morbus Cushing zur weiteren Abklärung der endokrinologischen Ambulanz zugewiesen. Die Patientin berichtete von einer ungewollten Gewichtszunahme von 10 kg und atypischen Fettablagerungen hauptsächlich im Bereich des Oberleibs in den letzen 10 Wochen. Eine ausführliche metabolische und endokrinologische Exploration wurde durchgeführt. Das pseudoathletische Aussehen der Patientin in Verbindung mit Stoffwechselstörungen und der vermutlich äthyltoxischen Leberschädigung führten letztendlich zur Diagnose einer Madelung-Krankheit. Dieser Fallbericht demonstriert die diagnostische Aufarbeitung dieser seltenen Erkrankung. Eine Osteoporose in Kombination mit einer ungewollten Gewichtszunahme und ungewöhnlicher Fettgewebsvermehrung führten letztendlich zur Diagnosestellung. Obwohl die therapeutischen Möglichkeiten limitiert sind, ist eine Diagnosestellung für die betroffenen Personen von extremer Wichtigkeit.SummaryMadelungs 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 Cushings 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 Madelungs disease and underwent a thorough examination with endocrine and metabolic evaluation of this rare condition and was finally diagnosed with Madelungs 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 Madelungs diseases, a rather unknown disorder likely to be under-diagnosed. Although treatment options are limited, a diagnosis is still important for the affected individual.

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.

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.