The Safety Profile of Vitamin D Supplements Using Real-World Data from 445,493 Participants of the UK Biobank: Slightly Higher Hypercalcemia Prevalence but Neither Increased Risks of Kidney Stones nor Atherosclerosis.

Background: Potential calcium-related adverse events of vitamin D supplement use have not been addressed in large-scale, real-world data so far. Methods: Leveraging data from the UK Biobank, encompassing 445,493 individuals aged 40-69, we examined associations of high 25-hydroxyvitamin (25(OH)D) levels ≥ 100 nmol/L and vitamin D supplementation with hypercalcemia (serum calcium > 2.6 mmol/L), kidney stones, and atherosclerosis assessments (pulse wave arterial stiffness index and carotid intima-medial thickness). Regression models were comprehensively adjusted for 49 covariates. Results: Approximately 1.5% of the participants had high 25(OH)D levels, 4.3% regularly used vitamin D supplements, and 20.4% reported regular multivitamin use. At baseline, the hypercalcemia prevalence was 1.6%, and 1.1% was diagnosed with kidney stones during follow-up. High 25(OH)D levels were neither associated with calcium-related adverse events nor atherosclerosis assessments. Vitamin D and multivitamin supplementation were associated with an increased prevalence of hypercalcemia (odds ratios and 95% confidence intervals: 1.46 [1.32-1.62] and 1.11 [1.04-1.18], respectively) but were neither associated with atherosclerosis nor future kidney stones. Conclusions: High 25(OH)D levels observable in routine care were not associated with any adverse outcome. Vitamin D users have a slightly higher prevalence of hypercalcemia, possibly due to co-supplementation with calcium, but without a higher atherosclerosis prevalence or risk of kidney stones.

Testing the dogma that total phospholipid fatty acid composition of blood plays a role in kidney stone pathogenesis, using a high-low risk human model: results from a pilot study.

Previous studies have suggested that ω-3 and ω-6 polyunsaturated fatty acid (PUFA) composition in plasma and red blood cell (RBC) total phospholipids plays a role in urolithiasis. Our aim was to test the robustness of this dogma by retrospectively comparing baseline profiles of these parameters in subjects from high- and low-stone-risk groups. The documented difference in stone occurrence in white (relatively common) (W) and black (rare) (B) subjects prompted us to select these groups as the high-low risk model for the study. Blood and urine samples were obtained from ten subjects in each group and were analysed for PUFAs and stone risk factors, respectively. Concentrations of linoleic acid (LA), eicosadienoic acid (EDA) and arachidonic acid (AA) in plasma and or/RBC total phospholipids were significantly higher in B. Differences in other PUFA profiles were also observed. There was no inter-group difference in AA/LA ratios. Urinary oxalate was significantly higher while urinary phosphate was significantly lower in B. We speculate that elevated AA in B might arise because of a possibly enhanced elongation of LA to EDA, as well as an enhanced ∆-8-desaturation of EDA to dihomo-gamma-linolenic acid (DGLA), which is the immediate precursor of AA. Alternatively, we speculate that the ∆-5-desaturation step of DGLA to AA might be more highly activated in this group. Irrespective of the mechanism, our observed inter-group differences in phospholipid PUFA composition are in conflict with previously published dogma which relates PUFA characteristics to high- and low-stone risk.

Different effects of γ-linolenic acid (GLA) supplementation on plasma and red blood cell phospholipid fatty acid composition and calcium oxalate kidney stone risk factors in healthy subjects from two race groups with different risk profiles pose questions about the GLA-arachidonic acid-oxaluria metabolic pathway: pilot study.

Fatty acid (FA) composition of phospholipids in plasma and red blood cells (RBC) can influence calciuria, oxaluria and renal stone formation. In this regard, the ratio of arachidonic acid (AA) and its precursor linoleic acid (LA) appears to be important. Administration of γ-linolenic acid (GLA) has been shown to increase the concentration of dihomo-gamma linoleic acid (DGLA) relative to AA indicating that it may attenuate biosynthesis of the latter. Such effects have not been investigated in race groups having difference stone occurrence rates. Black (B) and white (W) healthy males ingested capsules containing linoleic acid (LA) and GLA, for 30 days. Plasma and RBC total phospholipid (TPL) FA profiles, serum and 24 h urine biomarkers of hypercalciuria and urinary stone risk factors were determined on days 0 and 30. Data were tested for statistical significance using GraphPadInstat version 3.02. Concentration and percentage content of DGLA in plasma TPL increased in W but not in B. Arachidonic acid (AA) did not change in either group. There was no change in calcium excretion in either group but oxalate and citrate excretion increased in W. We suggest that elongation of GLA to DGLA may occur more rapidly than desaturation of DGLA to AA in W and that depressed activity of the enzyme elongase may occur in B. Calciuric and citraturic effects may be dependent on the quantity of LA or on the mass ratio of LA/GLA in the FA supplement. Questions about the mooted DGLA-AA-oxaluria pathway arise. We speculate that there exists a potential for using GLA as a conservative treatment for hypocitraturia. The observation of different responses in B and W indicates that such differences may play a role in stone formation and prevention.