Hyperuricemia is a metabolic disease characterized by elevated serum uric acid (SUA), the end-product derived from purine metabolism (1). With changes in lifestyle and diet in modern society, the increasing prevalence and incidence of hyperuricemia are likely to contribute substantially to the increasing burden of public health worldwide (2). Furthermore, it has already been associated with many diseases, including hypertension (3), cardiovascular diseases (4), diabetes mellitus (5, 6), metabolic syndrome (7), non-alcoholic fatty liver disease (8), and chronic kidney disease (9). Knowing risk factors for hyperuricemia is of critical importance to allow early interventions and mitigate cardiovascular disease burden.

Visceral adipose tissue has been regarded as an endocrine organ involved in numerous physiological processes such as lipid and glucose metabolism (10, 11). Recently, increasing evidence has suggested that visceral fat accumulation is correlated with elevated SUA levels. Takahashi et al. reported that the visceral fat area independently contributed to an elevated level of SUA in healthy men and was more accumulated in patients with gout (12). Zong and colleagues found that visceral fat was associated with SUA levels in people with type 2 diabetes mellitus (13). Yamada’s results were consistent with previous studies and demonstrated that the association between visceral fat and SUA was independent of lifestyle factors, including physical activity level, alcohol consumption, and smoking (14). Furthermore, visceral fat was more closely associated with high SUA levels compared to subcutaneous fat (15). Reduced visceral fat area was associated with a decrease in SUA level (16). Based on such evidence, visceral fat is suggested to be a significant risk marker for SUA.

Perirenal fat is a special visceral fat that is stored around the kidneys and has active abilities in metabolism regulation and adipokine secretion. The fibrous membrane and renal fascia separate perirenal fat from the other neighboring adipose tissues including pararenal fat and renal sinus fat (17). Due to its unique anatomy and physiological features, perirenal fat is known to be associated with many metabolic indexes (18–20). However, the association between perirenal fat and SUA has not been fully evaluated. In clinical studies, ultrasonography and computed tomography (CT) are widely used to measure the amount of perirenal fat. Compared to CT, ultrasonography is more convenient, easy-to-perform and without ionizing radiation. However, previous studies only measured a single thickness of perirenal fat on a specific layer via ultrasonography, which was insufficient to quantify the perirenal fat content (21, 22).

The inferior perirenal fat has the most abundant fat considering the non-uniform distribution of the perirenal fat (17). In our study, the inferior perirenal fat was measured longitudinally, transversally, and anterior-posteriorly by ultrasound, which was a more robust and precise approach to quantifying the amount of perirenal fat. Then, we conducted a cross-sectional study to explore the association between PrFV and SUA among Chinese adults.

To our knowledge, this study was the first evaluation to assess the association of ultrasound-derived PrFV with SUA among Chinese adults. And our results demonstrated that perirenal fat accumulation was independently and positively associated with SUA levels.

Several studies have explored the association between perirenal fat and SUA in patients with chronic kidney disease and/or type 2 diabetes, but the results were not well-established. D’Marco et al. found that the thickness of the perirenal fat was significantly correlated with SUA in patients with a GFR<60 mL/min/1.73m², and patients with type 2 diabetes accounted for 28% of this study population (22). Lamacchia and colleagues investigated combined para- and perirenal fat thickness was independently and positively correlated with elevated SUA levels in patients with type 2 diabetes (24). However, the ultrasonographic methodology in this study could not distinguish between perirenal fat and pararenal fat. Besides, in patients with type 2 diabetes, Fang et al. confirmed that perirenal fat thickness was positively related to SUA in a single correlation analysis (25).

Perirenal fat can be measured by CT and ultrasonography. Although CT is a full-scale measurement, ultrasonography is faster, cheaper, and without radiation. In addition, some researchers proved that inter-operator repeatability assessed by the difference between ultrasonography and CT was just 3.2 percent (21). Thus, ultrasonography is more suitable to quantify perirenal fat in large-scale clinical studies. Instead of the single-thickness measured in the above studies, we presented a novel method of measuring the volume of the inferior perirenal fat in three dimensions using ultrasonography. This novel approach provided a more accurate quantification of perirenal fat because the adipose tissue mainly depots at the lower renal pole (17). Naturally, further studies are needed to verify this method.

Compared with previous studies, we ruled out confounding by diabetes mellitus or chronic kidney disease, as glucometabolic disorder and renal dysfunction influence uric acid metabolism (26, 27). Then we performed qualitative and quantitative analyzes of PrFV, and the data were tested with multiple covariates. In our analysis, we found that SUA level was significantly correlated with BMI and WC, which were common indicators of adiposity in clinical practice, consistent with previous studies (28, 29). However, in multivariable generalized linear models, PrFV had a significant positive correlation with SUA, independent of BMI, WC, and other confounders, highlighting the important role of perirenal fat in uric acid metabolism. For the first time, we described the linear association between PrFV and SUA by fully adjusted restricted cubic spline that there was about a 0.53 mg/dL increase in SUA per 1-fold increase in PrFV (β=0.53, 95%CI 0.02-1.04, P for nonlinearity=0.637). These findings help better understand the association of PrFV with SUA.

There were several possible mechanisms that may explain the association between PrFV and SUA. First, the imbalance between urinary urate production and excretion contributes to the elevated level of SUA (30). As the subjects in our study had a normal renal function, overproduction might be the main cause of the strong link between perirenal fat and SUA. Uric acid can be produced and secreted by adipose tissue except for the liver and skeletal muscle (31). Excess adipose tissue characterized by hypoxia and active lipid metabolism increased uric acid synthesis and secretion (28, 32). Second, adiponectin (33)has a negative correlation with SUA (33). Increased perirenal fat accumulation can lead to lower adiponectin production (34), thus resulting in the increasing SUA level. Third, inflammation may play a role. Visceral adipose tissue is strongly correlated with inflammatory burden (35). On the other hand, elevated SUA levels are associated with inflammatory conditions (36–38). Therefore, increased inflammation in subjects with the highest PrFV tertile may be responsible of elevated SUA levels. Furthermore, elevated SUA induces fat accumulation through increased intracellular and mitochondrial oxidative stress (39), forming a vicious circle.

There were certain limitations in this study. We cannot explain the causal relationship between SUA and PrFV considering the design of the cross-sectional study. The sample size was limited as this study was a sub-analysis of previously collected data from 2 clinical studies. As a single-center study, the results may not be representative of the other ethnic population. Therefore, further large-scale prospective cohort studies are required to investigate the association. Moreover, we didn’t collect the dietary information which also may influence the adipogenesis and SUA level (40).

In conclusion, our study demonstrated a linear and positive association between PrFV and SUA, suggesting a possible role of PrFV in the management of SUA. Further studies are necessary to confirm the associations and underlying mechanisms.

The original contributions presented in the study are included in the article. Further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by the Institutional Review Board of the First Affiliated Hospital of Nanjing Medical University. The patients/participants provided their written informed consent to participate in this study.

MJ: Conceptualization, Formal analysis, Writing-Original draft. ML: Resources, Investigation. CL, LJ, QH, and TW: Investigation. JL: Writing–review, and editing. XK: Writing–review and editing, Supervision. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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