6. Observational Studies
Some studies have shown a positive association between urinary calcium excretion and 25-hydroxyvitamin D serum levels in adult stone formers [56,57]. Other authors did not find a relationship between 25-hydroxyvitamin D and urine calcium excretion or prevalent kidney stone disease. In the National Health Nutrition Examination Survey (NHANES) III cross sectional study, high serum 25-hydroxyvitamin D concentrations were not associated with prevalent kidney stones (reported history or nephrolithiasis) [58]. A retrospective study performed in 169 patients with nephrolithiasis did not show a relationship between serum 25-hydroxyvitamin D level and 24-h urine calcium excretion [59].
In a prospective analysis of 193,551 participants in the Health Professionals Follow-up Study (HPFS) and Nurses’ Health Studies (NHS) I and II, performed by Ferraro et al. there was no statistically significant association between vitamin D intake and risk of stones in the HPFS and the NHS I groups but potentially a higher risk in the NHS II group (Hazard Ratio 1.18, 95% Confidence Interval 0.94, 1.48, p for trend = 0.02) [60]. Of note, the NHS II study has been performed more recently and women included in the NHS II study had a daily intake of vitamin D (mainly due to supplementation) that was much more significant than in the previous studies. It may be hypothesized that this increase in vitamin D intake may have enhanced stone risk in this specific cohort.
Although the role of 25-hydroxyvitamin D serum levels in kidney stone formation has been discussed, the role of calcitriol is not a matter of debate. For instance, Taylor et al. compared calcium and phosphorus regulatory hormones and the risk of incident symptomatic kidney stones in a case-control study including 356 incident stone formers and 712 controls [61]. Baseline plasma levels of 25-hydroxyvitamin D were similar in both groups but higher plasma calcitriol levels were independently associated with a higher risk of symptomatic stones. Interestingly, several studies did not find an association between urinary calcium excretion and 25-hydroxyvitamin D serum levels when taking into consideration all stone formers, but identified a strong correlation when considering hypercalciuric stone formers only [29,62]. This point is critical and highlights that patient phenotype and kidney stone analysis should be assessed cautiously. Actually, vitamin D metabolism influences urinary calcium excretion, but all kidney stones are not calcium-dependent. Although calcium oxalate is the main component of 60 to 80% of all urinary calculi, there is strong evidence that calcium oxalate stones may result from hypercalciuria but also from hyperoxaluria and/or low diuresis, sometimes in the absence of metabolic disorder [4,63,64,65].
A recent meta-analysis based upon six case-control studies and one randomized controlled trial reported in the literature investigated the relationship between circulating 25-hydroxyvitamin D and the risk of stone formation [15]. Data were available for 451 kidney stone formers and 482 controls. The results provided evidence that kidney stone formers had significantly higher levels of 25-hydroxyvitamin D than controls, both in European and Asian populations. Finally, in another meta-analysis, Hu et al. investigated the association between circulating vitamin D levels and urolithiasis; twenty-two observational studies involving 23,228 participants were included [16]. Among them, 19,718 were controls and 3510 were stone formers. Within the latter group, more precise distinction was made regarding calcium excretion. The main conclusion of the meta-analysis was that calcitriol was significantly increased in stone formers compared to controls while 25-hydroxyvitamin D was similar in both groups. However, hypercalciuric stone formers had significantly higher calcitriol levels but also higher 25-hydroxyvitamin D serum levels than normocalciuric patients and controls.