As is well-known, kidney stone is a common and recurring disease seriously affecting human health, and causes increasing medical and economic burden. However, the specific pathogenesis of renal stones is still unclear. In addition to immune and inflammatory reactions, intestinal flora, and dietary regulation that significantly affect the stone formation process (Khan, Canales and Dominguez-Gutierrez 2021, Ticinesi, Nouvenne and Meschi 2019, Zhu, Liu, Lan et al. 2019), the role of trace elements in the occurrence and development of kidney stones has also attracted wide attention recently (Killilea, Westropp, Shiraki et al. 2015).
In this cross-sectional study, we used the public data from NHANES 2007–2018 cycles, which can symbolically represent the health of all residents in the USA. Results show that kidney stones are significantly associated with urinary cobalt (P = 0.0032). The prevalence of kidney stones grows gradually with the increase of urinary cobalt level. Additionally, the trend remains after adjustment for confounding factors.
To our knowledge, there is no direct experimental result to support this notion so far. Fortunately, many studies provide indirect evidence. Firstly, as for the mechanism of kidney stone formation, research shows that the increase of cobalt level can induce macrophage apoptosis, which leads to a decreased anti-inflammation ability and a higher risk of kidney stone formation (Xiao, Wu, Zhang et al. 2018). In addition, due to the higher incidence of thyroid cancer with increasing urine cobalt, more patients suffer from kidney stones (Edafe, Debono, Tahir et al. 2019, Murad and Eisenberg 2017, Royer, Mathieu and Balsan 1970). Moreover, the vascular endothelial growth factor (VEGF) is reportedly an essential contributor to renal stones. Our results demonstrate that the urine cobalt concentration rises along with the increase of VEGF expression. VEGF may act through several pathways to initiate the pathogenesis of the stone disease. Therefore, VEGF may function as a signpost for preventing stone formation (Bi, Liu, Li et al. 2010, Loboda, Jazwa, Wegiel et al. 2005, Sato, Virgona, Ando et al. 2014). In a word, the urine cobalt concentration can be highly viewed as a potential indispensable indicator of kidney stone diagnosis.
However, there are few reports on correlation between cobalt and kidney stones. An animal model shows that some trace elements of calcium oxalate urolithiasis change in different trends, as urine calcium, copper, iron, and vanadium levels increase, while urine cobalt level decreases (Furrow, McCue and Lulich 2017). In our opinion, the differences with our results can be attributed to some reasons. First, the researchers regarded the calcium oxalate stones of dogs as study samples, and second, the sample size was not big enough to further prove the credibility and representativeness of the results. Hence, it is urgent to conduct a systematic and comprehensive prospective study to clarify the controversy.
Furthermore, our result suggests that the proportions of obesity, smoking, and older people in kidney stone patients are growing gradually, and these types of patients are likely to have lower content of adiponectin (Achari and Jain 2017, Chełchowska, Gajewska, Maciejewski et al. 2020, Higham, Bostock, Booth et al. 2018, Kadowaki, Yamauchi, Kubota et al. 2006, Komiyama, Wada, Yamakage et al. 2018). The decline of adiponectin, an adipocytokine with the ability of anti-inflammation and anti-lipid peroxidation, contributes to a relatively high risk of stone diseases. In a word, adiponectin plays a potential role in stone formulation. Moreover, heavy activity can accelerate the loss of body fluid and urine concentration, so the urine cobalt level increases with the rising prevalence of kidney stones (Mao, Zhang, Xu, et al. 2021).
As we all know, the main types of kidney stones recognized by researchers are calcium oxalate, calcium phosphate, uric acid, cystine, and infectious stones (Bostanghadiri, Ziaeefar, Sameni et al. 2021). Analysis of the nature and composition of the stones indicates that the stones contain many trace elements (e.g. Fe, Zn, Sr, Se, Cd, and Co) in addition to the major elements (e.g. Ca, P, K, Na, Mg). The contents of trace elements in different types of stones and different parts of the same stone may differ (Keshavarzi, Yavarashayeri, Irani et al. 2015). Currently, the cobalt level in the human body can be observed through many objective indicators, of which urinary cobalt is the most feasible and economical one. Urinary cobalt can reflect the exposure of the human body to cobalt and can be used to detect human cobalt content (Junqué, Grimalt, Fernández-Somoano et al. 2020, Kettelarij, Nilsson, Midander et al. 2016). Over-accumulation of cobalt in the human body may cause kidney stones, hard metal lung disease, pulmonary edema, papillary thyroid carcinoma, allergic dermatitis, and other severe diseases (Knoop, Görgens, Geyer et al. 2020, Lantin, Vermeulen, Mallants et al. 2013, Leyssens, Vinck, Van Der Straeten et al. 2017, Van Der Meeren, Lemaire, Coudert et al. 2020). Cobalt is mainly excreted through urine. Therefore, the temporary storage and excretion of cobalt through the kidneys affect the external morphology of crystal formation and accelerate or slow down crystallization, probably causing the formation of kidney stones (Killilea, Westropp, Shiraki, et al. 2015). The above results suggest the potential role of urinary cobalt in calcium oxalate urolithiasis and prompts us to further analyze the relationship between urinary cobalt and kidney stones and to explore the possible etiology and pathophysiology of stone formation. These results also contribute to formulating safer and more effective standardized measures to prevent and treat kidney stones. Moreover, urinary cobalt content can reflect human exposure to cobalt, so it may provide a basis for developing a comprehensive cobalt exposure guide in the future and plays a critical role in the prevention and screening of kidney stones.
The major advantage of this study is that the representative population includes a multi-ethnic population from the USA. The large sample size also allows us to conduct in-depth analysis. However, there are some limitations and deficiencies. Firstly, due to the feature of the cross-sectional study, we cannot determine whether higher or lower urinary cobalt concentrations will affect the changes in kidney stone disease over time, and cannot assess the causal relationship between the two. Secondly, the data do not include information such as the size, quality, or type of kidney stones, and we were not permitted to conduct deeper analysis. In addition, we excluded pregnant women, because pregnancy has some effects on urinary cobalt content and kidney stones formation (Reinstatler, Khaleel and Pais 2017). Therefore, the findings of this study cannot be applied to this type of population. Finally, we do not rule out the biases caused by other potential confounding factors that were not adjusted here, such as food intake, and sleep hours.