Introduction
Obesity is recognized as a heterogeneous condition, in which individuals with similar levels of body mass index (BMI) may have distinct metabolic, cardiovascular (CV), and renal risk [
1]. Variation in body fat distribution provides a potential explanation for some of these observations. As such, excess visceral adipose tissue (VAT) compared to subcutaneous adipose tissue (SAT) is particularly associated with the presence of adverse metabolic risk factors, CV disease, and chronic kidney disease (CKD) [
2]. In addition to VAT, ectopic fat accumulation, i.e., storage of fat in non-adipose tissues, is also related to organ dysfunction [
3]. A well-known example is intrahepatic lipid accumulation leading to hepatic dysfunction [
4]. More recently, accumulation of fat in the renal sinus, a compartment located at the medial border of the kidney that contains renal vessels, calices, nerve fibers, and lymphatic channels, was suggested to increase risk of renal disease [
5,
6]. As such, in cross-sectional studies involving overweight individuals with and without type 2 diabetes (T2D), accumulation of renal sinus fat (RSF) was shown to independently associate with reduced estimated glomerular filtration rate (eGFR) [
7,
8] and CKD (defined as eGFR < 60 mL/min/1.73 m
2 [
9,
10].
Several mechanisms have been put forward to explain this association. First, RSF has been associated with systemic hypertension, which is a driver of CKD [
11,
12]. Notably, this association is independent of other adipose tissue compartments [
7,
11,
13]. Second, by compressing various renal structures, reduced tissue perfusion and tubular flow may occur [
8]. Third, in analogy to adipocytes from perivascular adipose tissue (PVAT), RSF adipocytes may secrete pro-inflammatory adipokines leading to renal inflammation, fibrosis and dysfunction [
7,
14,
15]. Fourth, RSF could modulate renal hemodynamics by secreting vasoconstrictive factors, as several studies have demonstrated PVAT to modulate vascular tone and skeletal muscle perfusion [
16]. Whether this mechanism of altered renal hemodynamics is present in T2D patients remains unknown. Therefore, we aimed to evaluate the role of RSF on renal hemodynamic regulation in overweight patients with T2D with normal kidney function.
Discussion
The current study is the first to assess the relation between MRI-measured RSF and renal hemodynamics as measured by gold-standard inulin (GFR) and PAH (ERPF) clearance techniques. In this cohort of T2D patients without overt CKD, we demonstrate that RSF, after correction for multiple potential confounding factors including age, VAT, MAP, sex, and BMI, is positively associated with renal vascular resistance.
Diabetic kidney disease (DKD) has become the leading cause of CKD and end-stage kidney disease (ESKD), and with the ever-increasing prevalence of obesity and T2D, this global health issue is likely to expand in the future. Despite multifactorial treatment aimed at reducing established renal risk factors (including dietary advices to reduce overweight, smoking cessation, amelioration of hyperglycemia, blood pressure- and albuminuria-lowering by blockers of the renin–angiotensin–aldosterone (RAS) system and lipid-lowering by statins) residual risk to develop ESKD remains high [
23]. This highlights the need for improved insight into the pathophysiology of CKD associated with obesity and diabetes, allowing for development of novel therapeutic approaches.
In this respect, RSF has received attention in the past. Although increased fat total mass is associated with various metabolic abnormalities as well as adverse cardiorenal outcome, specific adipose tissue depots were demonstrated to convey different risks for specific diseases. For RSF, it was demonstrated that increased fat at this anatomical location is associated with hypertension as well as lower eGFR, statistically independent of fat accumulation in other compartments [
7,
8]. In the present study, we add inulin clearance measurement of GFR to previous studies, which reported negative associations between RSF and eGFR (using MDRD, Cockcroft–Gault, or CKD-EPI equations), to show that increased RSF also shows a negative association with measured GFR and thus with renal function [
7,
9]. These results are especially important for the T2D patients, in which eGFR has proven to be systematically underestimated [
24].
Several mechanisms have been put forward by which increased fat deposition in the renal sinus may impair kidney function, beyond an increment in systemic blood pressure. First, due to compression of various renal structures, intrarenal pressure may result in less medullary perfusion and reduced tubular flow, which, in addition to inducing renal hypoxia, may stimulate increased renal sodium reabsorption [
25]. In our analyses, however, no association was observed between RSF and fractional sodium excretion. Second, accumulating evidence suggests that RSF might act as a PVAT depot and like the adipocytes from increased PVAT, RSF adipocytes might exhibit altered metabolism and secrete pro-inflammatory cytokines [
3]. This paracrine effect from the adipocytes could lead to renal damage through local inflammation, lipotoxicity, oxidative stress, and fibrosis [
7,
14]. Although we did not measure markers of oxidative stress or urinary inflammatory cytokines, we found no association between RSF and urinary levels of kidney injury molecule (KIM)-1 or neutrophil gelatinase-associated lipocalin (NGAL). Third, RSF could modulate arterial vascular tone and renal hemodynamics by secretion of vasoconstrictive factors, in analogy with PVAT in skeletal muscle, thereby altering renal function. Renal hemodynamics have received much attention in recent decades as the two classes of drugs that provide renoprotection in T2D patients, the RAS blockers, and sodium-glucose cotransporter (SGLT)-2 inhibitors, do this by beneficially altering (intra)renal hemodynamics. In the present analysis, we could relate RSF to renal hemodynamics due to our gold-standard measured GFR and ERPF from which we calculated filtration fraction and renal vascular resistance. We observed, even after correction for VAT, MAP, sex, and BMI that higher RSF associated with increased renal vascular resistance, which likely drives the lower GFR at the hemodynamic level. Estimated afferent arteriolar pressure shows a similar association with RSF. The increment in renal vascular resistance is relevant as this parameter, often estimated with Doppler ultrasonography-derived renal resistance index, has been shown to be associated with albuminuria and predicted progression of CKD in hypertensive patients [
26]. The mechanism by which RSF could modulate renal arteriolar resistance is unsure; however, a decrease in adiponectin production, probably due to the increased pro-inflammatory effects of macrophages or due to adipose tissue insulin resistance, leads to reduced ability to relax smooth muscle tonus [
14]. In addition, the production of the vasorelaxing factors such as nitric oxide (NO) by endothelial cells may be decreased by the altered secretion of PVAT adipocytes [
14], which could increase renal afferent resistance. Finally, it has been suggested that increased RSF leads to hypertension by activating RAS, possibly by mechanical compression of the low-pressure structure of the renal hilum [
9]. We, however, observed no association between RSF and efferent vascular resistance, where angiotensin II—the final product of RAS and a potent vasoconstrictor—is known to mediate its effects. In line, we could not link RSF with plasma renin levels, although the extensive use of RAS blockers in our group may have confounded these results. Due to the relatively small number of participants in our study population, subgroup analyses between the RAS-blocker group and the group not on RAS blockers did not provide us with reliable outcomes.
A significant strength of our study is the gold-standard methods for calculations of GFR and ERPF. On the other hand, this analysis has some limitations that need to be mentioned. First, the cross-sectional design of the study does not allow to address causality regarding the effects of RSF on renal hemodynamics. Second, our research was limited to the assessment of the quantity of the RSF, rather than the quality (i.e., possible biological/paracrine effects as observed for PVAT adipocytes). Therefore, from our results, we cannot draw conclusions about this possible paracrine regulation of vascular tone of RSF. Moreover, it would be interesting to repeat this research in a larger study population, to measure both kidneys and preferably use the Dixon technique to generate fat-only images from multi-echo MRI images for even more accurate fat quantification.
Further studies that modulate the amount of RSF, notably weight loss are warranted [
27], however, it will be difficult to tease out the specific effects of a reduction in RSF volume on renal function, when VAT and total body fat are concomitantly lowered. Furthermore, it will be interesting to measure proteins and cytokines that are secreted by RSF in different disease conditions such as obesity or T2D to better assess RSF function.
In conclusion, our results in T2D patients without overt CKD indicate that excess of RSF is associated with altered renal hemodynamics most notably with increased renal vascular resistance. As increased ERVR is associated with CKD and CKD progression, modulating RSF may provide a novel therapeutic approach to reduce the DKD burden.
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