This study was conducted with the primary objective of determining whether plasma S-klotho levels were independently related to hyperuricemia risk. As part of this study, we analyzed five NHANES cycle samples to reflect the overall middle-aged and elderly population in the United States. According to our results, there is a negative correlation between plasma S-Klotho and hyperuricemia in the entire sample population, and this relationship has a saturation effect, meaning the correlation between them ends when S-Klotho reaches 850.0 pg/ml. In addition, S-Klotho has a higher effect on uric acid metabolism in middle-aged people compared with elderly people. As compared to women, men who have higher levels of plasma S-Klotho are more protected against hyperuricemia. Over the past few decades, hyperuricemia has become a significantly prevalent condition among middle-aged and elderly individuals. There may be a variety of causes for this result including high purine diet, obesity, insufficient exercise, an unhealthy lifestyle, and others[23–25]. High serum uric acid levels are the main cause of gout. With a high uric acid level for long periods of time, urate crystals will be deposited in the joints and cause pain and inflammation. However, due to the phenomenon of asymptomatic hyperuricemia, high serum uric acid levels are rarely recognized and valued in middle-aged and elderly individuals[26]. According to current studies, hyperuricemia is associated with population mortality[27], affects the occurrence and progression of heart and kidney disease, and can be used as a predictor of obesity and metabolic syndrome[28–30]. A cohort study of people with heart failure found that hyperuricemia increases the risk of progression in patients with heart failure[31]. In our study, we found that the plasma levels of S-Klotho may have a protective effect against hyperuricemia in middle-aged and elderly people, so it is important to understand the effect of S-Klotho on hyperuricemia for middle-aged and elderly people, as well as clarify the potential benefits and risks of S-Klotho in these population groups.
Until now, only one study has reported the effect of serum uric acid level on S-klotho[32], however, it has not evaluated its effect on uric acid metabolism in middle-aged and elderly individuals from the perspective of plasma S-klotho, or whether hyperuricemia is correlated with S-Klotho. Consequently, there was no evidence linking plasma S-Klotho levels to hyperuricemia in middle-aged and elderly individuals prior to this study. However, from the point of view of S-Klotho participating in cellular pathways and regulating metabolism in the body, the results we observed may be reasonable. The S-Klotho protein is a transmembrane protein that is a component of the endocrine fibroblast growth factor (FGF) receptor[33]. FGF23 is a phosphoric acid hormone, and its mechanism of action can regulate the increased uptake of inorganic phosphate by the body. When osteocytes secrete FGF23, the increase of FGF23 level can down-regulate the level of sodium-dependent phosphate cotransporter in proximal tubules. In addition, S-Klotho forms a receptor complex after binding to FGF23, which can play a physiological role in the parathyroid gland, down-regulates serum parathyroid hormone levels and activity, reduces calcium cycling, and increases urinary phosphate excretion[34–37]. Consequently, we hypothesize that the negative correlation between plasma S-Klotho levels and hyperuricemia may be owing to the FGF23/S-Klotho endocrine axis, and this may also explain the saturation effect between S-Klotho and hyperuricemia from another aspect.
In subgroup analyses, we observed a potential effect of age in the relationship between plasma S-Klotho and hyperuricemia, especially among middle-aged individuals (40–65 years old). In this study, those with higher plasma S-Klotho levels tended to be younger and had lower levels of creatinine and urea, which is consistent with the protective effect of S-Klotho on the kidneys from renal damage. As a classic anti-aging gene, Klotho is mainly expressed in the kidney, and its expression level is negatively correlated with age. Current studies have confirmed that dysregulation of the FGF23-Klotho signaling pathway is significantly associated with the occurrence and progression of CKD, and leads to hyperphosphatemia and endothelial dysfunction[38]; in a mouse model of S-Klotho deficiency, the researchers also found evidence of renal impairment due to impaired urinary phosphate excretion[39]. Consequently, on the one hand, the amount of expression of S-Klotho decreases with advancing age, and on the other hand, the elderly have a worse kidney function and a lower urate excretion as compared with the middle-aged population, which is prone to hyperuricemia. Therefore, the differential effects of S-Klotho observed in different age groups may be the result of comprehensive factors.
To our knowledge, this is the first study to examine the association between plasma S-Klotho and hyperuricemia using population samples from NHANES. Considering that we included multi-ethnic populations and conducted the analysis in line with guideline recommendations, our results might be closer to what actually occurs in the U.S. population when it comes to the relationship between S-Klotho and hyperuricemia. Furthermore, we performed a subgroup analysis of these data and found a saturation effect between S-klotho and hyperuricemia, which represents the strength of this study. However, since this study is a cross-sectional survey, we cannot give an accurate causal relationship between hyperuricemia and plasma S-Klotho. Additionally, considering the subject's history of gout and the possibility that drug treatment may have an impact on hyperuricemia, they were not included in the final study model. Therefore, it cannot be ruled out that they may have an impact on the final result as confounding factors. In addition, since the study found that S-Klotho may have a circadian rhythm and temporal variation[40–41], there may be potential interference with the final results due to the different blood collection times from the subjects. This aspect needs to be further explored and clarified in future studies.