Alterations in regulators of the renal-bone axis, inflammation and iron status in older people with early renal impairment and the effect of vitamin D supplementation.

CONTEXT: Chronic kidney disease (CKD) leads to alterations in fibroblast growth factor 23 (FGF23) and the renal-bone axis. This may be partly driven by altered inflammation and iron status. Vitamin D supplementation may reduce inflammation. OBJECTIVE AND METHODS: Older adults with early CKD (estimated glomerular filtration rate (eGFR) 30-60 ml/min/1.73 m2; CKDG3a/b; n = 35) or normal renal function (eGFR >90 ml/min/1.73 m2; CKDG1; n = 35) received 12,000, 24,000 or 48,000 IU D3/month for 1 year. Markers of the renal-bone axis, inflammation and iron status were investigated pre- and post-supplementation. Predictors of c-terminal and intact FGF23 (cFGF23; iFGF23) were identified by univariate and multivariate regression. RESULTS: Pre-supplementation, comparing CKDG3a/b to CKDG1, plasma cFGF23, iFGF23, PTH, sclerostin and TNFα were significantly higher and Klotho, 1,25-dihydroxyvitamin D and iron were lower. Post-supplementation, only cFGF23, 25(OH)D and IL6 differed between groups. The response to supplementation differed between eGFR groups. Only in the CKDG1 group, phosphate decreased, cFGF23, iFGF23 and procollagen type I N-propeptide increased. In the CKDG3a/b group, TNFα significantly decreased, and iron increased. Plasma 25(OH)D and IL10 increased, and carboxy-terminal collagen crosslinks decreased in both groups. In univariate models cFGF23 and iFGF23 were predicted by eGFR and regulators of calcium and phosphate metabolism at both time points; IL6 predicted cFGF23 (post-supplementation) and iFGF23 (pre-supplementation) in univariate models. Hepcidin predicted post-supplementation cFGF23 in multivariate models with eGFR. CONCLUSION: Alterations in regulators of the renal-bone axis, inflammation and iron status were found in early CKD. The response to vitamin D3 supplementation differed between eGFR groups. Plasma IL6 predicted both cFGF23 and iFGF23 and hepcidin predicted cFGF23.

Early renal impairment affects hormonal regulators of calcium and bone metabolism and Wnt signalling and the response to vitamin D supplementation in healthy older adults.

Bone and renal metabolism are regulated by common factors and there is extensive cross-talk between these organs (the 'renal-bone-axis'). Ageing is associated with physiological changes including reduced bone mass, renal function and tissue sensitivity to regulatory hormones, impacting the renal-bone axis. We aimed to investigate the influence of estimated Glomerular Filtration Rate (eGFR) on plasma concentrations of vitamin D metabolites, Wnt signalling and bone metabolism in a dose ranging vitamin D3 RCT (12,000 IU, 24,000 IU, 48,000 IU/month for 1 year; n = 379, >70 y) with a baseline eGFR > 30 mL/min/1.73 m2. Participants were categorised on basis of eGFR (≥60 or mL/min/1.73 m2) based on 5 commonly used algorithms for eGFR. Differences between eGFR categories were tested with ANCOVA. Before supplementation commenced, a lower eGFR was associated with significantly higher concentrations of c-terminal and intact Fibroblast Growth Factor-23 (cFGF23; iFGF23), intact Parathyroid Hormone (iPTH) and Sclerostin (SOST) and lower Klotho, 1,25-dihydroxy Vitamin D (1,25(OH)2D) and Dickkopf-related Protein 1 (DKK1) concentrations. Differences between eGFR groups in 25-hydroxy Vitamin D (25(OH)D), 24,25-dihydroxy Vitamin D (24,25(OH)2D) and iPTH were only detected with eGFR based on Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Modification in Diet for Renal Disease (MDRD-4) algorithms. Differences in Bone Mineral Density and Content (BMD; BMC) and bone turnover markers were detected only with Cockcroft-Gault (CG). Pre- and post- supplementation comparisons showed differences in the response to supplementation by eGFR group. Plasma 25(OH)D, 24,25(OH)2D, 1,25(OH)2D and DKK1 increased and iPTH and C-terminal telopeptide (CTX) decreased in both groups. Plasma iFGF23, bone specific alkaline phosphatase (BAP) and Procollagen 1 intact N-terminal Propeptide (PINP) increased and phosphate decreased only in the group with eGFR ≥ 60 mL/min/1.73 m2. Findings were largely consistent across all eGFR algorithms. Post-supplementation, cFGF23, iFGF23, iPTH and SOST remained significantly higher in the lower eGFR group. Plasma 1,25(OH)2D and Klotho did no longer differ between eGFR groups. This was found for all eGFR algorithms, with the exception of iPTH and iFGF23, which were not significantly different with eGFR based on CG. Differences in BMD and BMC were detected with CKD-EPI-creatinine and MDRD-4 but not GC. This study showed that even a moderate decline in eGFR is associated with alterations in vitamin D metabolism, Wnt signalling and bone turnover markers. Renal function influenced the response to vitamin D supplementation. Supplementation increased Vitamin D metabolites in the group with moderate renal impairment to concentrations comparable to those found in the group with normal renal function. However, although CTX decreased, an increase in bone formation markers was not found in the group with eGFR 60 mL/min/1.73 m2. In conclusion, vitamin D supplementation had beneficial effects on markers of the renal-bone axis in older people with both normal and impaired renal function.

Vitamin D Supplementation for 12 Months in Older Adults Alters Regulators of Bone Metabolism but Does Not Change Wnt Signaling Pathway Markers.

Vitamin D status and supplementation regulates bone metabolism and may modulate Wnt signaling. We studied the response of hormonal regulators of bone metabolism, markers of Wnt signaling and bone turnover and bone mineral density (BMD) and bone mineral content (BMC) in a randomized vitamin D intervention trial (12,000 IU, 24,000 IU, 48,000 IU/mo for 1 year; men and women aged >70 years; n = 379; ISRCTN35648481). Associations with total and free 25(OH)D concentrations were analyzed by linear regression. Baseline vitamin D status was (mean ± SD) 25(OH)D: 40.0 ± 20.1 nmol/L. Supplementation dose-dependently increased total and free 25(OH)D concentrations and decreased plasma phosphate and parathyroid hormone (PTH) (all p < 0.05). The procollagen 1 intact N-terminal (PINP)/C-terminal telopeptide (CTX) ratio, C-terminal fibroblast growth factor-23 (cFGF23), and intact FGF23 (iFGF23) significantly increased with no between-group differences, whereas Klotho was unchanged. 1,25(OH)2D and PINP significantly increased in the 24 IU and 48,000 IU groups. Sclerostin (SOST), osteoprotegerin (OPG), receptor activator of NF-κB ligand (RANKL), BMD, BMC, and CTX remained unchanged. Subgroup analyses with baseline 25(OH)D <25 nmol/L (n = 94) provided similar results. Baseline total and free 25(OH)D concentrations were positively associated with 1,25(OH)2D, 24,25(OH)2D (p < 0.001), vitamin D binding protein (DBP) (p < 0.05), BMD, and BMC (p < 0.05). Associations with PTH (p <0.001), cFGF23 (p < 0.01), and BAP (p < 0.05) were negative. After supplementation, total and free 25(OH)D concentrations remained positively associated only with 24,25(OH)2D (p < 0.001) and DBP (p < 0.001) and negatively with estimated glomerular filtration rate (eGFR) (p < 0.01). PTH and SOST were significantly associated only with free 25(OH)D. There were no significant relationships with BMD and BMC after supplementation. The decrease in PTH and increase in PINP/CTX ratio suggest a protective effect of supplementation on bone metabolism, although no significant effect on BMD or pronounced changes in regulators of Wnt signaling were found. The increase in FGF23 warrants caution because of its negative association with skeletal and cardiovascular health. Associations of total and free 25(OH)D with biomarkers were similar and known positive associations between vitamin D status and BMD were confirmed. The change in associations after supplementation might suggest a threshold effect. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Vitamin D Supplementation for Patients with Chronic Kidney Disease: A Systematic Review and Meta-analyses of Trials Investigating the Response to Supplementation and an Overview of Guidelines.

A large proportion of patients with chronic kidney disease (CKD) are vitamin D deficient (plasma 25-hydroxyvitamin D (25(OH)D) < 25 or 30 nmol/L per UK and US population guidelines) and this contributes to the development of CKD-mineral bone disease (CKD-MBD). Gaps in the evidence-base for the management of vitamin D status in relation to CKD-MBD are hindering the formulation of comprehensive guidelines. We conducted a systemic review of 22 RCTs with different forms of vitamin D or analogues with CKD-MBD related outcomes and meta-analyses for parathyroid hormone (PTH). We provide a comprehensive overview of current guidelines for the management of vitamin D status for pre-dialysis CKD patients. Vitamin D supplementation had an inconsistent effect on PTH concentrations and meta-analysis showed non- significant reduction (P = 0.08) whereas calcifediol, calcitriol and paricalcitol consistently reduced PTH. An increase in Fibroblast Growth Factor 23 (FGF23) with analogue administration was found in all 3 studies reporting FGF23, but was unaltered in 4 studies with vitamin D or calcifediol. Few RCTS reported markers of bone metabolism and variations in the range of markers prevented direct comparisons. Guidelines for CKD stages G1-G3a follow general population recommendations. For the correction of deficiency general or CKD-specific patient guidelines provide recommendations. Calcitriol or analogues administration is restricted to stages G3b-G5 and depends on patient characteristics. In conclusion, the effect of vitamin D supplementation in CKD patients was inconsistent between studies. Calcifediol and analogues consistently suppressed PTH, but the increase in FGF23 with calcitriol analogues warrants caution.

Vitamin D and Ageing.

One hundred years has passed since the discovery of vitamin D as the active component of cod-liver oil which cured the bone disease rickets. Since then our knowledge of vitamin D has expanded tremendously and has included recognition of the importance of UV radiation as a source of the vitamin as well as the discovery of the vitamin as a nutrient, a pro-hormone and a potent steroid hormone with a major role in calcium and bone metabolism. In the last 25 years or so, the discovery of the vitamin D receptor in over 30 different body tissues together with the existence of the alpha-1-hydroxylase enzyme in these tissues provided evidence of a pleiotropic role of vitamin D outside its classical role in the skeleton. These important discoveries have provided the basis for the increasing interest in vitamin D in the context of nutritional requirements for health including the prevention of chronic diseases of ageing. The recent publication of the Dietary Reference Intake report on vitamin D and calcium by the North American Institute of Medicine (IOM) is the most comprehensive report to date on the basis for setting nutritional requirements for vitamin D. This chapter will summarize the nutritional aspects of vitamin D and discuss the changes in vitamin D metabolism and requirements with ageing. It will summarize key evidence on the relationship between vitamin D status and some of the main ageing related health outcomes including bone, muscle and cognitive health as well as survival focusing on the published literature in very-old adults (those >= 85 years of age).

Vitamin D and bone health outcomes in older age.

The aim of this review is to summarise the evidence linking vitamin D to bone health outcomes in older adults. A plethora of scientific evidence globally suggests that large proportions of people have vitamin D deficiency and are not meeting recommended intakes. Older adults are at particular risk of the consequences of vitamin D deficiency owing to a combination of physiological and behavioural factors. Epidemiological studies show that low vitamin D status is associated with a variety of negative skeletal consequences in older adults including osteomalacia, reduced bone mineral density, impaired Ca absorption and secondary hyperparathyroidism. There seems to be inconsistent evidence for a protective role of vitamin D supplementation alone on bone mass. However, it is generally accepted that vitamin D (17·5 µg/d) in combination with Ca (1200 mg/d) reduces bone loss among older white subjects. Evidence for a benefit of vitamin D supplementation alone on reducing fracture risk is varied. According to a recent Agency for Healthcare Research and Quality review in the USA the evidence base shows mixed results for a beneficial effect of vitamin D on decreasing overall fracture risk. Limitations such as poor compliance with treatment, incomplete assessment of vitamin D status and large drop-out rates however, have been highlighted within some studies. In conclusion, it is generally accepted that vitamin D in combination with Ca reduces the risk of non-vertebral fractures particularly those in institutional care. The lack of data on vitamin D and bone health outcomes in certain population groups such as diverse racial groups warrants attention.

Type 2 diabetes management in nurse-led primary healthcare settings in urban and rural Cameroon.

AIMS: To implement a protocol-driven primary nurse-led care for type 2 diabetes in rural and urban Cameroon. METHODS: We set-up three primary healthcare clinics in Yaounde (Capital city) and two in the Bafut rural health district. Participants were 225 (17% rural) patients with known or newly diagnosed type 2 diabetes, not requiring insulin, referred either from a baseline survey (38 patients, 17%), or secondarily attracted to the clinics. Protocol-driven glucose and blood pressure control were delivered by trained nurses. The main outcomes were trajectories of fasting capillary glucose and blood pressure indices, and differences in the mean levels between baseline and final visits. RESULTS: The total duration of follow-up was 1110 patient-months. During follow-up, there was a significant downward trend in fasting capillary glucose overall (p<0.001) and in most subgroups of participants. Between baseline and final visits, mean fasting capillary glucose dropped by 1.6 mmol/L (95% CI: 0.8-2.3; p< or =0.001). Among those with hypertension, blood pressure also decreased significantly for systolic and marginally for diastolic blood pressure. No major significant change was noticed for body weight. CONCLUSIONS: Nurses may be potential alternatives to improve access to diabetes care in settings where physicians are not available.

Parathyroid hormone and rates of bone formation are raised in perimenopausal rural Gambian women.

To investigate rates of bone turnover and calcium homeostasis in Gambian women, we recruited 103 peri- and postmenopausal women, aged 45 to 80+ years and 11 women of reproductive age. Fasting blood was analyzed for plasma osteocalcin, PTH, 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)(2)D], total- and bone-specific alkaline phosphatase. Plasma and urinary calcium, inorganic phosphate, sodium, potassium, creatinine, and albumin and urine free deoxypyridinoline (Dpd) was also measured. Samples from 20 premenopausal and 31 postmenopausal women from Cambridge, UK were analyzed, using the same methodology for comparison. For the Gambian women, peak calcium excretion occurred at around 50 years of age. For women aged > or =45 years, calcium excretion decreased by 3.0% per year of age (SE 1%; P < 0.005). In this age group, 25(OH)D also decreased with age (P < 0.005). Urinary sodium output, pH, and titratable acid output decreased (all P < 0.05) and total alkaline phosphatase (P < 0.005), osteocalcin (P < 0.005), and PTH (P < 0.05) increased with age. Comparisons were made between the following groups of Gambian and British women: premenopausal, early (age 55-64 years)- and late (age 65+ years)-postmenopausal. Gambian women of all ages were lighter (P < 0.001), shorter (P < 0.01), and had higher plasma bone-specific alkaline phosphatase activity (P < 0.05) and higher concentrations of osteocalcin (P < 0.05), PTH (P < 0.001), 1,25(OH)(2)D (P < 0.001), and 25(OH)D (P < 0.001). There were no consistent differences in calcitonin, while urinary free Dpd outputs were lower in the Gambians (P < 0.001). Plasma calcium, phosphate, and albumin (P < 0.01) were significantly lower. Urinary calcium, phosphate, sodium, and potassium excretion were lower, particularly in the postmenopausal group (P < 0.001). Although Gambian urine pH was more acidic, titratable acid output was lower (P < 0.01). These data show that Gambian women with low dietary calcium intakes and good vitamin D status have low urinary calcium excretion and that menopausal changes in calcium and bone metabolism among Gambian women are similar to those seen in other populations. In addition, they demonstrate that Gambian women of all ages have raised plasma PTH and 1,25(OH)(2)D concentrations and raised markers of osteoblast activity. We postulate that high endogenous PTH concentrations may be beneficial to bone health in Gambian women, removing fatigue damage and improving bone quality.

Exposure over the life course to an urban environment and its relation with obesity, diabetes, and hypertension in rural and urban Cameroon.

BACKGROUND: This study aimed to assess the association between lifetime exposure to urban environment (EU) and obesity, diabetes, and hypertension in an adult population of Sub-Saharan Africa. METHODS: We studied 999 women and 727 men aged > or =25 years. They represent all the adults aged > or =25 years living in households randomly selected from a rural and an urban community of Cameroon with a 98% and 96% participation rate respectively. Height, weight, blood pressure, and fasting blood glucose were measured in all subjects. Current levels of physical activity (in metabolic equivalents [MET]) were evaluated through the Sub-Saharan African Activity Questionnaire. Chronological data on lifetime migration were collected retrospectively and expressed as the total (EUt) or percentage (EU%) of lifetime exposure to urban environment. RESULTS: Lifetime EUt was associated with body mass index (BMI) (r = 0.42; P < 0.0001), fasting glycaemia (r = 0.23; P < 0.0001), and blood pressure (r = 0.17; P < 0.0001) but not with age. The subjects who recently settled in a city (< or =2 years) had higher BMI (+2.9 kg/m(2); P < 0.001), fasting glycaemia (+0.8 mmol/l; P < 0.001), systolic (+23 mmHg; P < 0.001) and diastolic (+9 mmHg; P = 0.001) blood pressure than rural dwellers with a history of 2 years EU. EU during the first 5 years of life was not, on its own, associated with glycaemia or BMI. However, both lifetime EUt and current residence were independently associated with obesity and diabetes. The association between lifetime EUt and hypertension was not independent of current residence and current level of physical activity. CONCLUSIONS: This study suggests that for the study of obesity and diabetes, in addition to current residence, both lifetime exposure to an urban environment and recent migration history should be investigated.