In this study of 560 patients with ccRCC, we found that IFI was an independent predictor of high-grade ccRCC in both males and females. Unlike previous studies, this result indicates that intermuscular adipose tissue, rather than visceral fat, is the most valuable component of abdominal fat for the pathological grading of ccRCC. In addition, SFI and VFI have sex-specific prognostic value in the pathological grading of ccRCC.

Epidemiological studies suggest that obesity may be a significant risk factor for kidney cancer [14, 15]. However, there exists a paradox between obesity and improved prognosis. The relationship of obesity to the pathological grade of kidney cancer remains unclear. Consistent with the findings of this study, Hu et al. reported that BMI was not a significant risk factor for high-grade ccRCC. This may be because BMI is a general concept that does not reflect the fat content, and the pathological grade of ccRCCs may be related to specific changes in the composition of one or more fat types.

Our study revealed significant differences in fat components between the sexes. Male patients had significantly higher BMI, VAT, TAT, and rVAT values than female patients, whereas female patients had significantly higher SAT values than male patients. Similar findings have been reported by Park et al. [16], and demonstrated sexual dimorphism based on anthropometric measurements, with males tending to accumulate more visceral fat and females accumulating more fat in the subcutaneous depot [17]. Therefore, consideration of sex in obesity-related studies is highly warranted.

Several studies have reported that visceral fat is associated with the pathological grade of RCC [11, 18, 19]. However, the results of these studies were inconsistent. According to Zhu et al. [11], VAT% (OR 1.06, 95% CI 1.02–1.09, p = 0.0018) was an independent prognostic predictor for a higher Furhman grade in patients with cT1a RCC. Hu et al. [19] reported similar findings and found that rVAT (OR 1.06, 95% CI 1.02–1.09, p = 0.0018) was the only predictor of pathological grade in female patients with ccRCC. However, Maurits et al. [12] found no association between visceral fat and the pathological grade of RCC. In the present study, VAT, VFI, IMAT, IFI, TAT, TFI, and rVAT were associated with the pathological grade of ccRCC in males, whereas only IMAT, IFI, and TAT were associated with the pathological grade of ccRCC in females. Although these results appear to be contradictory, meaningful conclusions can be drawn. First, there may be considerable heterogeneity by sex. Second, these studies agree that subcutaneous fat content is not related to the pathological grade of renal tumors. Lastly, the study by Maurits et al. [12] was based on a large sample size, whereas the studies by Zhu et al. [11] and Hu et al. [19] had a small sample size; therefore, the association between visceral fat and the pathological grade of kidney tumors may be weak or even unrelated. However, none of these studies calculated adipose tissue index to balance out the effect of body size, nor did they measured intermuscular fat and included it in further analyses.

In this study, we discovered that intermuscular fat was significantly higher, regardless of sex, in patients with high-grade ccRCC. We first identified IFI as an independent predictor of pathological grade in patients with ccRCC. Among the fat components, intermuscular fat has received little attention in cancer-related studies. Previous studies have found different mRNA expression patterns in visceral, subcutaneous, and intermuscular depots, indicating that each fat component represents a unique regulatory tissue [20, 21]. Similar to visceral adipose tissue, increased intermuscular fat is associated with poor physical and metabolic outcomes, including diabetes, chronic kidney disease, and cardiovascular disease [22,23,24,25]. Intermuscular fat has recently been shown by Yu et al. [26] to be a significant risk factor for major complications after primary total hip arthroplasty. Jeon et al. [27] reported that the intermuscular fat index is associated with breast cancer prognosis. This may be related to the fact that high-grade tumors promote an increase in intermuscular fat with antioxidant and anti-inflammatory effects. However, the underlying biological mechanism remains unclear. Investigations on human IMAT are essential for further adipose biology research.

In the present study, low VFI and low SFI were independent risk factors for high-grade ccRCC in men and women, respectively. Keehn et al. [18] reported that VAT may be associated with high pathological grade in patients with small renal masses. This is consistent with the results of our study. Visceral fat can secrete adipokines such as leptin and adiponectin [28]. Clinical studies have shown that low adiponectin is associated with tumorigenesis and poor prognosis [29, 30]. And SAT produces leptin and maintains insulin sensitivity, thus impairing tumor progression [31]. These may explain the association of higher VFI and SFI with lower tumor grade.

There are several limitations to this study. First, this was a single-center, retrospective study. Second, we only studied the fat area and did not explore the association between fat density and the pathological grade of ccRCC because the images were not obtained from plain CT scans. Third, this study is the first to suggest an association between intermuscular fat and kidney tumor grade. Larger confirmatory studies are needed to verify and evaluate this association.

In conclusion, intermuscular fat index is a valuable biomarker for the pathological grade of ccRCC and could be used as a reliable independent predictor of high-grade ccRCC for both males and females. Sex-specific differences in adipose tissue distribution contribute to the varying predictive values of ccRCC grades between males and females. This study provides valuable insights into the importance of considering sex-specific adipose tissue components in the pathological grading of ccRCC, potentially paving the way for personalized treatment approaches based on these specific fat depots.