Cost effectiveness of sodium zirconium cyclosilicate for the treatment of hyperkalaemia in patients with CKD in Norway and Sweden.

BACKGROUND: Hyperkalaemia is common in patients with chronic kidney disease (CKD) and is associated with a range of adverse outcomes. Historically, options for management of chronic hyperkalaemia in the outpatient setting have been limited. Novel oral potassium binders provide a safe, effective therapy for maintenance of normokalaemia in patients with CKD, but despite being approved for reimbursement in many countries, prescription data indicate uptake has been slower than anticipated. This analysis aimed to demonstrate the value to patients and the healthcare system of the potassium binder sodium zirconium cyclosilicate (SZC) for treatment of hyperkalaemia in patients with CKD in Norway and Sweden. METHODS: A published simulation model reflecting the natural history of CKD was adapted to the Norwegian and Swedish settings and used to predict long-term health economic outcomes of treating hyperkalaemia with SZC versus usual care. RESULTS: SZC was highly cost effective compared to usual care in Norway and Sweden, with incremental cost-effectiveness ratios of €14,838/QALY in Norway and €14,352/QALY in Sweden, over a lifetime horizon. The acquisition cost of SZC was largely offset by cost savings associated with reductions in hyperkalaemia events and hospitalisations; a modest overall increase in costs was predominantly attributable to costs associated with gains in life years compared with usual care. SZC remained cost effective in all scenarios examined. CONCLUSIONS: SZC was estimated to be cost effective for treating hyperkalaemia. Consequently, improving access to a clinically effective, safe and cost-effective therapy, such as SZC, may result in considerable benefits for CKD patients with hyperkalaemia.

Influence of multiple UV exposures on serum cobalamin and vitamin D levels in healthy females.

AIMS: Ultraviolet (UV) radiation is a major source for vitamin D production. Furthermore, UV destroys cobalamins (also called vitamin B12) in solution. However, data from humans are scarce. The aim of the present study was to clarify if UV exposure has any effect on serum cobalamins, as compared to vitamin D levels, in healthy volunteers. METHODS: This single-center, open observational study was conducted in a research institute: 23 non-pregnant, non-lactating, healthy, fair-skinned female subjects had their serum cobalamin and 25-hydroxyvitamin D (25(OH)D, the marker for vitamin D status) levels measured before and after exposure to UV. RESULTS: UV exposure increased serum 25(OH)D levels from 61.6 nmol/L to 88.5 nmol/L (44%; p < 0.001). A statistically insignificant decay in serum cobalamin levels from 300 pmol/L to 260 pmol/L (13%; p = 0.142) was observed in the volunteers after the first UV exposure; however, no additional decline of statistical significance was seen after subsequent exposures. CONCLUSIONS: Multiple exposure to UV radiation give a significant increase in 25(OH)D levels, but has no detrimental effect on cobalamin concentrations.

Vitamin D levels and dietary intake among patients with benign soft tissue tumors and sarcomas.

BACKGROUND: Calcitriol [1,25(OH)2D] is hypothesized to lower the risk of cancer via binding to the vitamin D receptor (VDR). VDRs are also found in benign and malignant cells of mesenchymal origin. To our knowledge, vitamin D levels and dietary intake have not been previously evaluated in patients newly diagnosed with benign and malignant mesenchymal tumors. PATIENTS AND METHODS: Forty-eight patients with benign soft tissue tumors and 25 patients with sarcoma had their serum 25-hydroxyvitamin D [25(OH)D], 1,25(OH)2D and parathyroid hormone levels measured, vitamin D intake scored and body mass index [BMI] calculated. RESULTS: Vitamin D deficiency [25(OH)D level<50 nmol/l] was observed in 19% and 28% of patients with benign tumor and sarcoma, respectively. CONCLUSION: Serum 25(OH)D, 1,25(OH)2D and parathyroid hormone concentrations, BMI and daily vitamin D intake did not differ significantly between the two groups of patients. Higher vitamin D intake or UV exposure is needed to ensure that all patients achieve sufficient vitamin D levels.

Increase in serum 25-hydroxyvitamin-D3 in humans after sunbed exposures compared to previtamin D3 synthesis in vitro.

Ultraviolet (UV) radiation is liable to cause skin cancer but it is the main source of vitamin D. Vitamin D photosynthesis takes place in skin at sub-erythemogenic UV doses, while larger exposures destroy vitamin D and increase DNA damage. Proper UV dosimetry is needed to obtain an optimal vitamin D status when skin cancer risk is minimal. A simple approach to such dosimetry using physically measured accumulated UV dose cannot provide a satisfactory quantification of vitamin D because of the complexity of the processes involved in vitamin D synthesis. A biological dosimeter of vitamin D synthetic UV radiation ('D-dosimeter') has been introduced earlier on the basis of an in vitro model of previtamin D photosynthesis. In the present study in vivo generation of 25-hydroxyvitamin D (25(OH)D) in serum of healthy volunteers exposed to UV radiation from the sunbed was accompanied by in vitro measurements of vitamin D formation using 'D-dosimeter'. It was found that the increase in serum 25(OH)D concentration depended both on the initial 25(OH)D level and on the cumulative sunbed exposure time. The observed linear correlation between in vivo and in vitro data can be used to estimate changes in vitamin D status after UV exposure using only one pre-exposure blood sample combined with further in vitro measurements.

Vitamin D status in healthy Romanian caregivers and risk of respiratory infections.

OBJECTIVES: To investigate the vitamin D status during winter of a healthy population of hospital employees and to assess the correlation between vitamin D status and risk of infections in the upper respiratory tract. DESIGN: One hundred and ten healthy volunteers answered a questionnaire on their solar exposure habits and vitamin D intake and delivered one blood sample for quantification of vitamin D level (serum 25-hydroxyvitamin D (25(OH)D) concentration) during December 2007-January 2008. At the end of the winter we screened for the occurrence of respiratory infections and sought associations with vitamin D status. SETTING: Bucharest, Romania, 45°N. SUBJECTS: One hundred and ten healthy hospital employees. RESULTS: Eighty per cent of participants were vitamin D deficient (25(OH)D level below 50 nmol/l). The main determinant of serum 25(OH)D was sun exposure during the summer previous to the study (P = 0·02 in multivariate analysis). Intake of vitamin D, BMI and age played no significant role for the level of 25(OH)D. Overall we found a non-significant negative correlation between 25(OH)D level and new cases of infection (Spearman correlation coefficient of -0·12, P = 0·2). CONCLUSIONS: Vitamin D status is alarmingly poor in active, relatively young women residing in Romania. If our results are reproduced by other investigations, action to improve vitamin D status at the population level is necessary. We were not able to show a statistically significant relationship between vitamin D status and infection risk in our material.

Vitamin D status in Norwegian children and adolescents with excess body weight.

OBJECTIVES: The prevalence of childhood and adolescent obesity has increased during the past decades. A high body mass index (BMI) is associated with a low vitamin D status. The purpose of this study was to determine the prevalence of vitamin D deficiency and insufficiency in Norwegian children and adolescents with excess body weight. METHODS: Vitamin D status and seasonal variations of 25(OH)D and 1,25(OH)(2)D were analyzed in 102 children and adolescents (70 girls and 32 boys), 8-19 yr of age, with overweight and obesity. RESULTS: Overall, 50% of the children and adolescents included in the study had a low vitamin D status (25(OH)D <75 nmol/L) and 19% had vitamin D deficiency (25(OH)D <50 nmol/L). This was most prevalent in adolescents. Only 42% of teenagers had 25(OH)D levels ≥75 nmol/L vs. 72% of preteens. Both 25(OH)D and 1,25(OH)(2)D showed seasonal variations. A peak in serum 25(OH)D concentrations was observed during the summer while the lowest values were seen during the spring. In contrast, serum 1,25(OH)(2)D had a peak during the spring and the lowest concentrations during the winter. CONCLUSIONS: The prevalence of vitamin D deficiency and insufficiency is higher in obese and overweight adolescents than in overweight children. This might be related to low outdoor activities and low vitamin D intake in teenagers. Seasonal variations of both the vitamin D metabolites were observed.

Serum 25-hydroxyvitamin D is a predictor of serum 1,25-dihydroxyvitamin D in overweight and obese patients.

Recent research suggests that 1,25-dihydroxyvitamin D [1,25(OH)(2)D], a steroid hormone that regulates calcium homeostasis, may also play a role in the development and progression of cancer, multiple sclerosis, cardiovascular, and other diseases. Decreased serum 1,25(OH)(2)D concentrations are often observed in overweight and obese patients. However, little is known about the factors that may influence 1,25(OH)(2)D renal synthesis, because it is generally accepted that serum 1,25(OH)(2)D concentration is strictly regulated by parathyroid hormone and serum concentrations of calcium and phosphorus. In this study, the associations among serum 1,25(OH)(2)D, serum 25-hydroxyvitamin D [25(OH)D], and body composition were analyzed in 1779 patients with excess body weight registered in a Metabolic and Medical Lifestyle Management Clinic in Oslo, Norway. According to our results, serum 25(OH)D, adiposity, age, season of blood sampling, and gender directly influence serum 1,25(OH)(2)D (r = 0.33; P < 0.001), with serum 25(OH)D being the strongest predictor for serum 1,25(OH)(2)D. The 1,25(OH)(2)D concentrations were 25.4 pmol/L (95% Cl: 19.3-31.5; P < 0.001) lower in the lowest 25(OH)D quartile to compared with highest quartile. A seasonal variation was observed for both vitamin D metabolites. Thus, our results suggest that in patients with excess body weight, serum 1,25(OH)(2)D concentrations were associated with 25(OH)D and varied during the year. Therefore, it may also be valuable to measure both serum 25(OH)D and 1,25(OH)(2)D for the evaluation of vitamin D status in overweight and obese persons.

The seasonality of pandemic and non-pandemic influenzas: the roles of solar radiation and vitamin D.

OBJECTIVES: Seasonal variations in ultraviolet B (UVB) radiation cause seasonal variations in vitamin D status. This may influence immune responses and play a role in the seasonality of influenza. METHODS: Pandemic and non-pandemic influenzas in Sweden, Norway, the USA, Singapore, and Japan were studied. Weekly/monthly influenza incidence and death rates were evaluated in view of monthly UVB fluences. RESULTS: Non-pandemic influenzas mostly occur in the winter season in temperate regions. UVB calculations show that at high latitudes very little, if any, vitamin D is produced in the skin during the winter. Even at 26°N (Okinawa) there is about four times more UVB during the summer than during the winter. In tropical regions there are two minor peaks in vitamin D photosynthesis, and practically no seasonality of influenza. Pandemics may start with a wave in an arbitrary season, while secondary waves often occur the following winter. Thus, it appears that a low vitamin D status may play a significant role in most influenzas. CONCLUSIONS: In temperate latitudes even pandemic influenzas often show a clear seasonality. The data support the hypothesis that high fluences of UVB radiation (vitamin D level), as occur in the summer, act in a protective manner with respect to influenza.

Obesity and increased risk of cancer: does decrease of serum 25-hydroxyvitamin D level with increasing body mass index explain some of the association?

Low levels of vitamin D and excess body weight are both factors associated with increased risk of cancer. The increased risk seems to be proportional to the increase in BMI, and to decrease in serum 25-hydroxyvitamin D (25(OH)D) level. Our earlier investigations suggest that serum 25(OH)D levels decrease with increasing BMI. Although the connection between cancer risk, BMI and vitamin D status might be arbitrary, it has not been discussed in the literature so far. In this study, we analyze data published in current meta-analysis, prospective studies, and systematic reviews on cancer-specific risk attributed to high BMI and low vitamin D status. The contribution of low 25(OH)D levels associated with high BMI to increased cancer risk was calculated for 13 vitamin-D-sensitive cancers with a focus on colorectal and breast cancer as the most frequently studied vitamin-D-sensitive cancer types. Our study suggests that a low vitamin D status may explain at least 20% of the cancer risk attributable to high BMI. The contribution of low 25(OH)D to the increased cancer risk with increasing BMI may be different for different cancer types. Thus, we find 40% for breast cancer, and 26 and 75% for colorectal cancer in men and women, respectively.

Seasonal variations of cancer incidence and prognosis.

The overall death rates are highest in the winter season in many countries at high latitudes. In some but not all countries, this is also true for more specific diseases such as cancer, cardiovascular diseases and influenza. For internal cancers we find no consistent, significant seasonal variation, neither of incidence nor of death rates. On the other hand, we find a significant seasonal variation of cancer prognosis with season of diagnosis in Norway. Best prognosis is found for summer and autumn diagnosis; i.e., for the seasons of the best status of vitamin D in the population. There were no corresponding seasonal variations, neither of the rates of diagnosis, nor of the rates of death which could explain the variations of prognosis. The most likely reason for this variation is that the vitamin D status in Norway is significantly better in summer and autumn than in winter and spring. Earlier, seasonal variations have been explained by circannual variations of certain hormones, but the data are not consistent.

Sunbeds as vitamin D sources.

The objectives of this work were: (1) To determine whether repeated exposures to small doses from a commercial sun bed (Wolff Solarium Super Plus 100 W) over 5 weeks gave less vitamin D than repeated exposures to twice as large, but still nonerythemogenic, doses. (2) To investigate whether the contribution to the vitamin D status from such sessions of exposures was dependent on the baseline status before the start of the sessions. (3) To determine the decay rate of the induced increment of vitamin D. The sun bed sessions raised the 25-hydroxyvitamin D levels from typical winter values to typical summer values. The mean value after exposure being 80 nm (+/-14) and the increase being 15 nm on average. Persons with the lowest initial levels got the largest increase. The level in this group was back to the pre-exposure level after 2-4 weeks. To maintain a summer level through the winter, when no vitamin D is produced by the sun in northern countries, one should consider increasing the recommended intake of vitamin D intake significantly, or encouraging the population to get moderate, nonerythemal sun bed exposures.

Sun and sun beds: inducers of vitamin D and skin cancer.

Solar radiation is both the main cause of all types of skin cancer, including cutaneous malignant melanoma (CMM), and the main source of vitamin D accompanied by its beneficial effects. The dilemma lies in that increased sun exposure could lead to an increase in skin cancers and yet is necessary for the better prognosis of internal cancers. Solar radiation varies in intensity and spectral composition with geographic location and time. Of central interest in the present context is that the UVA/UVB ratio can vary. Thus, the UVA/UVB ratio increases with decreasing solar elevation. The ratio is also larger for most sun beds than that in the midday sun, but similar to that in the afternoon sun. This may have large health implications, since vitamin D is exclusively generated by UVB, while UVA and UVB likely play a role in the onset of CMM. Sun and sun beds act similarly: one quantum of radiation at a given wavelength has the same biological effect, irrespective of the source from which it comes. The winter levels of vitamin D are 10 to 100% lower than the summer levels in most populations, but can be brought up to summer levels by moderate sun bed exposure. Doses of 200 IU of vitamin D per day are not sufficiently large to maintain a summer vitamin D status in winter. At high latitudes (>40 degrees) the sun provides no vitamin D in winter. A number of epidemiological studies, interventional studies, animal studies and cell experiments show that vitamin D reduces the risk and/or prognosis of internal cancers. Populations living at high latitudes would probably benefit from moderately increasing their exposure to UVB to provide a good vitamin D status.

Solar radiation, vitamin D and cancer incidence and mortality in Norway.

Solar radiation is of fundamental importance for human development and health: On the one hand, too much of it can lead to skin ageing and skin cancer, whilst on the other, too little of it can result in vitamin D deficiency, and, thereby lead to high incidence and poor prognosis of internal cancer as well as a number of other diseases. The following data, mostly from Norway, will be reviewed: Variation of ambient solar ultraviolet radiation (UV) and vitamin D status with season and latitude, variation of incidence rates and prognosis of skin cancer and variation of prognosis of internal cancer with latitude and season. In short, the following issues are discussed: 1) Vitamin D level varies with season, but probably not with latitude in Norway, because of an increased intake of vitamin D in the north; 2) Skin cancer incidence rates increase from north to south, as do annual fluence rates of UV radiation, while there seems to be a slight improvement in prognosis from north to south; 3) Prognosis of internal cancer is best for cases diagnosed in the seasons with the best vitamin D status, i.e. in summer and autumn; 4) Incidence rates of cutaneous melanomas have increased from 1960 to 1990, but have decreased slightly thereafter for young people; 5) Changes in sun exposure habits have taken place; 6) An increase in body mass index (BMI) of the population has occurred, which may have led to a worsening of the vitamin D status.

The dependency of vitamin D status on body mass index, gender, age and season.

BACKGROUND: Obesity is a rapidly growing health problem in most developed countries. Excess body weight is a risk factor for many somatic and even psychological disorders, including cardiovascular disease, type 2 diabetes mellitus, osteoarthritis and several cancer types. Recently, overweight and obesity have been shown to be related to low vitamin D status. MATERIALS AND METHODS: The 25(OH)D3 status was analyzed in a population of 2,126 patients registered in a Metabolic and Medical Lifestyle Management Clinic in Oslo, Norway. Seasonal variation and prevalence of vitamin D deficiency were assessed in different body mass index (BMI), sex and age categories. RESULTS: For both sexes and both age groups (<50 years and > or = 50 years) there was a significant decrease of serum 25(OH)D3 levels with increasing BMI. Surprisingly, not only were the 25(OH)D3 levels negatively correlated with BMI, but the serum 1,25(OH)2D3 levels were also. The seasonal variation of serum 25(OH)D3 was highest in young (<50 years) non-obese men. The prevalence of vitamin D deficiency was highest in individuals with BMI > or = 40, being as high as 32% among women and 46% among men. CONCLUSION: The 25(OH)D3 level, as well as its seasonal variation and the prevalence of vitamin D deficiency, are all dependent on BMI, and age separately. The results of the study suggest that 1 in 3 women and 1 in 2 men with BMI > or = 40 are vitamin D deficient.

The vitamin D status among Tibetans.

UVB from the sun and intake from food are the only human sources of vitamin D. Tibet is a unique region for comparisons of these sources: (1) it lies at a low latitude and at a high altitude and has very large annual fluences of UVB; (2) the traditional Tibetan food is poor in vitamin D. Blood samples were taken from 63 persons of different age, with different occupations and staying at different places. UVB doses at these places were measured. The samples were analyzed by a standard radioimmune assay for determination of the serum concentration of 25 hydroxyvitamin D (25(OH)D). The main finding was that among nomads, there seems to be severe vitamin D deficiency (serum levels of 25(OH)D<30 nM). We tentatively propose that the low level of 25(OH)D of nomads is related to their clothing and sun exposure habits. For persons of other occupations (students, teachers and farmers) the levels are higher, although a significant fraction of these persons also have lower levels than 75 nm, by many regarded as a limit for insufficiency related to a number of negative health conditions. The annual dose of vitamin D-generating UVB is about five times larger in Lhasa than in Oslo. Despite this, the average vitamin D status seems to be similar, except in the case of nomads. This phenomenon is certainly related to food habits. In conclusion, the 25(OH)D status among nomads in Tibet appears to be alarmingly low. However, for people of other occupations the status is more normal.

Seasonal variation of 1,25-dihydroxyvitamin D and its association with body mass index and age.

Under most normal conditions the serum level of 1,25-dihydroxyvitamin D is constant throughout the year, due to tight biochemical regulation. In contrast to this, the level of 25-hydroxyvitamin D is variable through the year, being largest in late summer, due to photosynthesis in the skin. The vitamin D status is usually assessed by measuring the level of the latter vitamin D derivative, rather than that of the presumably most active derivative 1,25(OH)2 vitamin D.We here show that for persons with a high body mass index (BMI) there is a significant seasonal variation, not only of 25(OH) vitamin D, but also of 1,25(OH)2 vitamin D. The variation seems to be largest for those with the poorest vitamin D status. Furthermore, there seems to be a correlation between the levels of the two vitamin D metabolites, indicating that the regulation of 1,25(OH)2 vitamin D is not always tight, notably in persons with high BMI.

Colon cancer: prognosis for different latitudes, age groups and seasons in Norway.

The survival of colon cancer patients in Norway, as determined three years after diagnosis, is dependent on the season of diagnosis. This has been attributed to seasonal variations of the vitamin D status. Since solar radiation and food are the human sources of vitamin D, we divided Norway in three regions: The southeast region with a high annual dose of ultraviolet (UV) to the population, as evidenced by a high incidence rate of squamous cell carcinoma of the skin (SCC), the midwest region and the north region with low annual UV doses. The latter region is characterized by a high consumption of vitamin D, mainly through fish intake. Vacations to southern latitudes were equally frequent for all the three geographical regions. Two age groups were analyzed separately (< or =65 years and >65 years), since the photosynthesis of vitamin D(3) in skin decreases with age. In all three regions, and in both age groups, the survival was highest for summer and autumn diagnosis. The seasonal effect was slightly, but not significantly, better for the younger than for the older age group. The effect was similar for all three geographical regions, irrespective of SCC incidence.

Prostate cancer survival is dependent on season of diagnosis.

BACKGROUND: We have earlier found that the prognosis for several cancers is dependent on season of diagnosis. More recently, both prostate cancer incidence and mortality have been shown to increase with increasing latitude, which probably relates to photosynthesis of vitamin D. METHODS: The 3 year survival of prostate cancer patients has been analyzed with the Cox regression method for two age groups at different latitudes in Norway. RESULTS: Patients diagnosed during the summer and autumn had the best prognosis (Ralative risk (RR) death 0.8; 95% CI 0.75-0.85). Similar results were observed in three regions of the country that differ with respect to annual fluences of solar UV radiation, incidence rates of squamous cell carcinoma (SCC) and intake of fish. Furthermore, similar relationship between the season and survival was seen among patients 65 years old, although the younger group had a slightly larger advantage of summer and autumn diagnosis. CONCLUSIONS: The seasonal effect on prognosis may be related to the seasonal variations of calcidiol (the marker of vitamin D status). The lack of latitude effect and the similarity of prognosis for different age groups may be related to higher consumption of vitamin D in food in the north region and to increase of such consumption with age.

Changes in risk of death from breast cancer with season and latitude: sun exposure and breast cancer survival in Norway.

The Norwegian counties can conveniently be divided in three groups with different annual UV exposures and different incidence rates of squamous cell carcinoma (SCC) of the skin. In view of the hypothesis that latitude and season of diagnosis may play a role for breast cancer progression, the prognosis of breast cancer as determined for summer and winter diagnosis, were evaluated in the three residential regions. Two age groups were analysed separately (stratification at 50 years). For all regions, and for all ages, the prognosis was best for women diagnosed in the summer season (Relative risk (RR) of death was 15-25% lower for summer diagnosis versus winter diagnosis). There was no significant seasonal variation of the number of new cases. For women diagnosed before the age of 50, a geographical gradient in cancer prognosis was also found (RR of death 0.6, 95% CI: 0.5-0.7 for cases diagnosed in southeast Norway and RR of death 0.8, 95% CI: 0.6-1.1 for diagnosis in the north of Norway). This is in agreement with a 1.5 times larger annual UV exposures and 3-4 times larger incidence rates of SCC in the southeast region when compared with the north region. For women diagnosed after the age of 50, no significant difference was found between the three regions. Despite a 17% higher vitamin D intake from food in north of Norway no difference in cancer survival was found for diagnosis during winter (when no significant differences in the levels of UV exposure can be detected between regions). The overall data support our earlier hypothesis that season of diagnosis and therapy start improves the survival for breast cancer.