Fatty kidney is a common condition, present in nearly one-third of our community-based sample. Fatty kidney is associated with both hypertension and CKD based on cystatin-C. These associations persisted after accounting for measures of generalized or abdominal adiposity, suggesting that renal sinus fat may have an independent association with renal function. In contrast, the observed associations of renal sinus fat with other cardio-metabolic traits were generally attenuated after accounting for overall VAT, which is consistent with the hypothesized localized impact of renal sinus fat and provides further support for the potential unique role of this fat depot in hypertension and renal dysfunction.
The association of obesity with the development of CKD4–6
is well-established, although the pathogenic mechanisms are not fully understood. Ectopic fat accumulation is one of several mechanisms proposed to explain these associations. Renal sinus fat accumulation has been observed in small imaging studies of children (n=15)26
and adults (n=6)27
with normal renal function. The association of renal sinus fat with hypertension and creatinine clearance was recently studied in 205 participants from the Pulmonary Edema and Stiffness of the Vascular System study, a study designed to assess predictors of congestive heart failure in older individuals.15
In this study, patients with SBP≥160mmHg or DBP≥100mmHg had higher levels of renal sinus fat, quantified by magnetic resonance imaging, than in those with blood pressure<160/100mmHg, although associations with SBP, DBP, and renal function were not observed,15
perhaps due to the small sample of highly selected individuals.
Animal models of diet-induced obesity provide additional insight into potential mechanisms involved in the pathogenesis of renal sinus fat. Rabbits with diet-induced obesity undergo a 61% increase in renal sinus mass, primarily driven by increases in fat within the renal sinus.14
This increase in renal sinus mass is observed concomitantly with increases in blood pressure.14
It has been hypothesized that renal sinus fat deposition leads to increases in renal interstitial pressure through the compression of vessels exiting the kidney, including the renal vein and lymph vessels.9
This potential mechanism is supported by studies in dog and rat models in which renal vein compression leads to increased renal interstitial pressure, kidney volume, and, in the presence of volume expansion, increased sodium reabsorption in the loop of Henle and decreased sodium excretion.10–13
Increased tubular reabsorption and retention of sodium is also observed in the dog model of obesity-related hypertension,28
a model for the development of obesity-related hypertension in humans.29
Alternative animal models of obesity reported lipid accumulation within the renal parenchyma, supporting proposed mechanisms of obesity leading to kidney damage and hypertension through lipotoxicity, oxidative stress, inflammation, and fibrosis.30,31
Obese mice fed a high-fat diet developed lipid accumulation in the glomeruli and proximal tubules in addition to albuminuria, increased SBP and oxidative stress, and a larger glomerular tuft area and mesangial matrix when compared to mice fed a low-fat diet.18
Zucker diabetic fatty rats exhibit greater lipid accumulation in the renal cortex when compared to pair-fed lean controls.17
Lipid accumulation within the renal parenchyma has also been described in humans.16
Overall, evidence from animal models supports the presence of obesity-related increases in renal lipid accumulation with concomitant structural and functional changes in the kidney and vasculature. However, it is uncertain whether these changes are specifically due to renal fat accumulation as compared to generalized weight gain and adiposity. Higher levels of BMI are among the strongest correlates of many ectopic fat depots.20,32,33
We have attempted to dissect the specific role of renal sinus fat as compared to generalized markers of adiposity and ectopic fat through our modeling structure and serial adjustment for BMI and VAT. While our findings are attenuated after accounting for each of these adiposity-related variables, the residual statistical significance suggests a potential independent association of renal sinus fat with hypertension and CKD. We have also addressed this issue by evaluating the trends in SBP and eGFRcys
with increasing renal sinus fat within narrower ranges of abdominal VAT; these findings further support an independent association with renal sinus fat. Finally, we did not observe an association with the presence of diabetes after accounting for abdominal VAT, which is in contrast to our prior work demonstrating consistent associations with VAT,20
and upper body subcutaneous fat.35
This suggests that potential mechanisms for the association of renal sinus fat with hypertension and CKD are unlikely due to high correlations among different fat depots and provides support for a unique and specific association between renal sinus fat and hypertension and CKD.
Similar to our previous findings investigating abdominal VAT and CKD,36
we observed in the present analysis that fatty kidney is associated with CKD when using cystatin-C based eGFR but not creatinine-based eGFR. One potential explanation is that cystatin-C may be a more sensitive marker for assessing renal function as compared to serum creatinine in older populations,37
given that serum creatinine is predominately derived from muscle tissue and that overall muscle mass is lower in older individuals.23,38
However, our results may also reflect potential confounding due to the independent association of cystatin-C with non-renal factors39,40
Cystatin-C is secreted by adipose tissue41
and the prevalence of cystatin-C based CKD may be overestimated in overweight and obese individuals when compared to the prevalence based on the MDRD Study equation.42
While it is important to consider the role of adiposity in cystatin-C production, if our association observed for fatty kidney and cystatin-C based CKD were solely due to confounding by overall adiposity, the association would have been completely attenuated after adjusting for BMI or abdominal VAT. Conversely, we observed a significant residual association upon further adjustment. Therefore, secretion of cystatin C by adipocytes is unlikely to fully explain our observations.
The Framingham MDCT cohort is a large, well-characterized, community-based sample with multiple measures of adiposity, allowing for adjustment of several important confounders and further adjustment for generalized and central adiposity. Using computed tomography, we were able to develop a non-invasive, reproducible method to quantify renal sinus fat accumulation in a community-based setting. Some limitations warrant mention. This is an observational study, which limits our ability to assess the causality of our findings. Given the cross-sectional design, we were also unable to assess the temporality of our observed associations. Our study sample is comprised of Caucasian participants. Based on this, our findings may not be generalizable to populations consisting of other racial or ethnic groups.