Discussion
We found suggestive evidence that circulating concentrations of 25(OH)D3 are inversely associated with the risk of RCC, such that participants with concentrations of less than 25 nmol/L had approximately 20% greater risk than those with concentrations of 50 nmol/L. We also found that lower concentrations of 25(OH)D3 were nonlinearly associated with the risk of all-cause mortality after RCC diagnosis. Among the majority of participants, an inverse association was apparent, whereas higher concentrations of 25(OH)D3 also appeared to be associated with higher risk of death.
Previous reports of prospectively measured circulating 25(OH)D and the risk of kidney cancer have produced conflicting results. In accordance with our results, the Copenhagen City Heart Study, a cohort of 9,791 people, including 55 incident kidney cancer cases, reported that a 50% reduction in 25(OH)D was associated with higher risk (hazard ratio = 1.34, 95% CI: 1.04, 1.73). In contrast, the Vitamin D Pooling Project found no association in an analysis of 775 case-control pairs nested within 8 prospective cohorts. These discrepant results are not readily explicable. One difference between the Vitamin D Pooling Project and the present study is the method of adjustment for season. The Vitamin D Pooling Project used conditional logistic regression models adjusted for season of blood collection (summer vs. winter), with sensitivity analyses adjusted for seasonality by using the residuals from a local polynomial regression. In contrast, we directly modeled seasonality using smooth trigonometric functions. Another difference between the studies is that both the Vitamin D Pooling Project and the Copenhagen City Heart Study used a chemiluminescence immunoassay measuring both 25(OH)D2 and 25(OH)D3, whereas in the present study, we used liquid chromatography coupled with tandem mass spectrometry to quantify 25(OH)D3 specifically. That said, these methodological differences would seem unlikely to fully account for the discrepant results, which remain unexplained.
Although few studies have directly assessed vitamin D status, some investigators have taken a different approach, creating a predicted vitamin D score on the basis of established determinants of vitamin D concentrations. Joh et al. investigated predicted 25(OH)D concentrations (calculated on the basis of race, UVB flux, physical activity, BMI value, vitamin D intake, alcohol consumption, and postmenopausal hormone use) and risk of RCC among participants of the Nurses' Health Study and the Health Professionals Follow-up Study. They found a strong inverse association between predicted 25(OH)D and risk, such that a 10-ng/mL (approximately 25-nmol/L) increment in predicted score was associated with a 44% lower hazard of RCC. Although the magnitude of the estimated association is greater, this result is broadly consistent with our observation that incrementing 25(OH)D3 from 25 to 50 nmol/L is associated with approximately 20% lower risk. In contrast, studies of dietary sources of vitamin D alone have largely yielded null results, possibly because dietary sources do not contribute greatly to circulating vitamin D concentrations.
There are several plausible mechanisms that might underpin an association between vitamin D and RCC. For instance, it is possible that vitamin D modifies the effects of risk factors such as obesity, hypertension, or diabetes. Although we observed an indication that the association between 25(OH)D3 and RCC risk might be slightly stronger among those with BMI values of 30 of higher, statistical adjustment for systolic blood pressure or prevalent diabetes did not affect the estimates, suggesting a potential role of vitamin D beyond that of established risk factors. This is consistent with studies of human RCC cell lines and murine RCC, which have shown that vitamin D species can inhibit tumor cell proliferation, angiogenesis, and metastasis. Conversely, given the critical role of the kidneys in vitamin D metabolism, it is possible that the observed association is driven by perturbed vitamin D metabolism as a consequence of early kidney dysfunction. Although the association remained consistent throughout follow-up and was not affected by adjustment for circulating creatinine, we cannot completely rule out the possibility that early renal dysfunction was the cause, rather than the result, of the observed distribution of circulating vitamin D.
Many researchers have investigated circulating vitamin D and all-cause mortality in general populations. Consistent with our observation, many studies have reported higher risk of death for people with low vitamin D concentrations. This suggests that the association observed in our study may not be specific to RCC survival, but rather a reflection of a general phenomenon. Our observation that high levels of 25(OH)D3 might be associated with higher risk of death is consistent with results from the Uppsala Longitudinal Study of Adult Men, which also suggest a U-shaped association. Despite this accord, further studies are required to investigate the intriguing possibility that both low and high concentrations are associated with all-cause mortality.
The principal limitation of our study is that 25(OH)D3 was measured using a single blood sample drawn in adulthood. Although individual vitamin D measurements are reasonably reproducible, intraindividual variation may still be important. Further, it is possible that a single measurement in adulthood does not capture exposure to vitamin D in an etiologically relevant period.
Our study has several strengths. Importantly, our sample included participants from 10 European countries from different geographical latitudes and with a wide range of 25(OH)D3 concentrations. Biospecimen handling was standardized, and quantification of circulating 25(OH)D3 took place in a single laboratory, thus minimizing systematic interlaboratory variation. The prospective design of our study, in which 25(OH)D3 concentrations were assessed using blood collected prior to diagnosis, minimizes the chance that any differences between cases and controls are caused by existing tumors. Further, the availability of detailed information on potential confounders—particularly the inclusion of circulating cotinine as a biomarker of current smoking intensity and creatinine as a marker of renal function—affords additional confidence that the observed associations were not caused by residual confounding.
In conclusion, we found that low concentrations of 25(OH)D3 were associated with higher risk of RCC as well as lower all-cause mortality among RCC cases. High concentrations of 25(OH)D3 might also be associated with increased risk of all-cause mortality among RCC cases.