Adipose Tissue as Risk Factor for Kidney Disease

Abstract

Obesity remains the leading risk factor for increased risk of acute kidney diseases and increased risk for progression to chronic kidney disease. Accumulation of excess adipose tissue in various body compartments is an underpinning characteristic of obesity. In the human body, adipose tissue in the body is mainly stored as subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT). Adipose tissue is biologically active and may interact with metabolic processes. Excess adipose tissue accumulation may be pathogenic through adverse endocrinologic or immunologic activity, and metabolic changes affect kidney function by decreasing the glomerular filtration rate (eGFR). Estimation of GFR is mainly based on serum biomarkers such as serum creatinine and or cystatin C. Adipocytes release cystatin C in a time-dependent manner and are not associated with serum creatinine. Pathophysiological mechanisms linking adipose tissue and cystatin C in humans remain unknown, and potential crosstalk mechanisms related to adipose tissue and kidney diseases remain scarce. In the clinical context, assessment of kidney function is based on the eGFR calculation based on serum biomarkers measurement, and whether other inflammatory parameters may help to explore the pathophysiological link or mechanism between adipose tissue and kidney function through biomarkers exploration remains unknown. This chapter aims to provide further insights into the mechanisms that link adipose tissue and kidney crosstalk by exploring kidney function biomarkers.

1. Introduction

Obesity, coupled with other co-morbidities such as diabetes and hypertension, remains the leading risk factor for increased risk of acute kidney diseases and increased risk for progression to chronic kidney disease, which leads to premature mortality globally [1]. The main characteristic of obesity is an accumulation of excess adipose tissue in various body compartments. However, adipose tissue in the body is mainly stored as subcutaneous adipose tissue (SAT), which plays a vital role in thermoregulation, and as visceral adipose tissue (VAT), which has a higher degree of metabolic activity [2]. Biological functions of adipose tissue may interact with metabolic processes, excessive mass alone may be pathogenic through adverse endocrinologic or immunologic activity, and metabolic changes may affect kidney function [3]. Glomerular filtration rate (GFR) [4] is the most helpful index for kidney function assessment [4], and reduction of GFR may indicate acute kidney injury (AKI) or chronic kidney disease (CKD) [5]. GFR estimation is mainly based on serum biomarkers such as serum creatinine and or cystatin C [6, 7, 8]. Both biomarkers are widely used in clinical practice; however, relatively imprecise GFR estimates remain, which may affect both acute and chronic illness, and such imprecision may result in the misclassification of patients with an estimated GFR of less than 60 ml per min/1.73 m³ that might lead to unnecessary therapeutic interventions. When using serum creatinine as a biomarker for GFR estimation, several factors, such as muscle mass, physical activity, and protein-rich food intake, may influence its levels. Cystatin C is considered an alternative to serum creatinine for estimating GFR and is less affected than serum creatinine. As non-glycosylated protein synthesized and released by most nucleated cells, filtered by glomerulus, and catabolized by proximal tubules, cystatin C may also be influenced by inflammation, thyroid gland, tobacco use, thyroid disease, and obesity. Adipose tissue, defined as VAT and SAT, has been reported to be associated with impaired kidney function when cystatin C was used for GFR determination [9, 10, 11]. Adipocytes release cystatin C in a time-dependent manner. Yet, pathophysiological mechanisms linking adipose tissue and cystatin C in humans remain unknown, and potential mechanisms related to adipose tissue and kidney diseases remain scarce. Despite the clinical assessment of kidney function being based on the eGFR calculation—based on biomarkers measurement, the pathophysiological link or mechanism between adipose tissue and kidney function and biomarkers remains unknown. This chapter aims to provide further insights into the mechanisms that link adipose tissue and kidney disease by exploring kidney function biomarkers.

2. Adipose tissue and kidney disease

Adipocites and preadipocites are components of the adipose tissue, which ordinarily cellular part consists of 50% fat cells and the remaining 50% as preadipocites containing vascular stroma, endothelial cells, fibroblasts and macrophages [2, 12]. The main functions of adipose tissue are thermogenesis and energy storage; therefore, there are two distinct types of adipose tissue in the human body: subcutaneous adipose tissue (SAT), which plays an essential role in thermogenesis with lesser metabolic activity or function, and visceral adipose tissue (VAT) as fat storage mainly located in the abdominal region that is metabolically active, with increased vascularization, sympathetic innervation, and β3-adrenergic receptors. Factors such as adipocyte apoptosis, preadipocyte differentiation, lipolysis, lipogenesis, adipocyte receptors, cytokines, and adipokine secretion differ for fat depots. Although SAT is thought to be protective, even excessive subcutaneous adipose tissue may become pathogenic [13]. Under the conditions of obesity, the accumulation of fatty tissue in the abdominal cavity and surrounding internal organs is characterized as visceral adipose tissue, which later is pathogenically implicated in endocrine functions [3]. VAT is represented as a significant risk factor for cardio-metabolic diseases, which later affect kidney function. Loss or damage of nephrons, the kidney’s functional units, is the underpinning pathophysiological pathway of kidney diseases. Within nephrons, podocytes are the fundamental cells of the glomerular barrier that selectively filter a range of macromolecules [14]. Podocytes are highly specialized and terminally differentiated cells that no longer can divide; therefore, malfunctioning or damaged podocytes can no longer be replaced. Thus, podocytes undergo hypertrophy to maintain the glomerular barrier integrity [15, 16].

Further, podocyte dysfunction or damage causes albuminuria, and increased albumin leak through the glomerular membrane promotes a pro-inflammatory reaction that can lead to interstitial inflammation and damage, leading to nephron dysfunction [17]. Adipose tissue, obesity-related glomeruli-associated damage is a concept proposed to describe the kidney function changes followed by glomerulopathy with podocyte damage and loss, glomerulosclerosis as a complex of kidney abnormality that includes glomerulomegaly and mesangial expansion, increased blood flow and hyper-filtration [18, 19]. A cascade of kidney function changes is directly linked to adipose tissue in early stages with reduced eGFR, followed by albuminuria, podocyte dysfunction, glomerulomegaly, glomerulosclerosis, and tubulointerstitial fibrosis. However, obesity with excess VAT, along with other risk factors or co-morbidities, indirectly contributes to kidney disease with a complex cascade of pathophysiological changes in the human body, such as increased systemic inflammation, the release of adipokines and cytokines, lipotoxicity, insulin resistance, renin-angiotensin system (RAAS) activation, and hypertension. Given that a decrease in GFR may indicate acute kidney injury (AKI) or chronic kidney disease (CKD), estimation of GFR based on biomarkers such as serum creatinine and cystatin C is the most reliable assessment of kidney function, the most widely used clinical practice.

Nevertheless, differences in tissue origin and production rates of compounds exist. The creatinine muscular source is well documented [4, 20], whereas the contribution of different organs in the production of circulating levels of cystatin C has been reported to be associated with VAT [10, 21], and similar findings have been found in an animal study [22]. Yet, mechanisms that relate adipose tissue and cystatin C remain unknown.

3. Adipose tissue pathophysiological mechanisms and kidney disease

3.1 Adipose tissue storage and kidney disease

The pathogenesis of the adipose tissue is significantly influenced by metabolic hormonal [23, 24] processes on how the adipose tissue is stored, through hypertrophy or hyperplasia, but also depending on the compartment of the human body where the adipose tissue is stored [2, 25, 26]. In positive caloric balance, metabolic processes or genetic factors determine how the adipose tissue is stored, whether adipocytes respond through hypertrophy or hyperplasia. In the adipogenic process, some factors may have different effects on adipocytes and non-adipocytes upon differentiation (adipocyte maturity and lipogenesis) or proliferation (new adipocytes from non-adipocytes) [27]. These two processes are driven by hormones such as glucocorticoids, angiotensinogen, and angiotensin II, which are closely related to metabolic disorders and fat storage deterioration [28, 29, 30]. The resulting hypertrophy compared to hyperplasia of fatty tissue, especially VAT versus SAT, in practical terms, has clinical implications given that it triggers adipose tissue paracrine activity, function, or dysfunction that promotes metabolic disorders such as type 2 diabetes mellitus, hypertension, and dyslipidemia [31, 32] and later affects the kidney function also. Alternatively, the location of adipose tissue is another crucial factor in whether fat depots have pathogenic potential. VAT, more accumulated in the abdomen or so-called abdominal adiposity, produces bioactive molecules and metabolism compared to less metabolically active SAT, which is accumulated and distributed in peripheral subcutaneous tissue.

Similarly, peri-organ adipose tissue, through metabolic activities, including the release of inflammatory factors and or lipolysis, may have a pathogenic impact on target organs, including kidneys [33]. In this context, accumulation of adipose tissue in the abdominal cavity and surrounding organs, mainly as VAT, represents a major risk for metabolic disorders leading to kidney diseases, indirectly and directly, as inner and/or outer ectopic VAT exacerbates the normal function of kidneys, similar liver steatosis, and within a period of time leading to chronic kidney disease. This condition is more recognizable as fatty kidney disease [34] and is characterized by the spread accumulation of adipose tissue and reduced function in general. Previously, a study assessing the role of intra-renal adipose tissue reported a strong association with VAT, hypertension, albuminuria, and decreased kidney function [35, 36]. Nevertheless, as suggested above, the intra- and extra-renal VAT interplays bidirectionally, negatively impacting kidney function by directly affecting kidney hemodynamics. These changes lead to hyper-filtration, albuminuria, and, finally, impairment in GFR rate due to glomerulosclerosis, indirectly exacerbating various metabolic and inflammatory risk factors [35].

3.2 Adipose tissue, inflammation, and kidney disease

Adipocytes, in particular VAT adipocytes, are metabolically active cells that produce hormonal factors such as adiponectin, leptin, resistin, and visfatin but also inflammatory factors such as cytokines, including tumor necrosis factor (TNF)-a, interleukin (IL)-6, and interleukin (IL)1β [3, 37]. Although adipocytes and cytokines are intimately involved in developing inflammation, free fatty acid release, oxidative stress, and insulin resistance, their mechanism of action is poorly understood. However, their action is attributed to activating the rennin-angiotensin-aldosterone system (RAAS) [38]. Adiponectin receptors are widespread within glomeruli cells, including podocytes [39], and in mice, reduced adiponectin levels have negatively impacted podocyte function [40]. Free fatty acid, glucose metabolism, and insulin resistance are inversely associated with adiponectin levels, and in obesity, adiponectin levels are decreased, whereas leptin levels are increased [41].

On the other hand, leptin increases proportionally with adipose tissue and is key to energy balance and homeostasis regulator [42]. While leptin levels in CKD increase, it is unclear whether such levels are related to decreased GFR, given that leptin is principally cleared via the kidneys. Leptin and adiponectin have established effects on kidneys [3], and adiponectin may be produced locally within the kidneys rather than acting in an autocrine inter-organ crosstalk manner by exerting metabolic and inflammatory functions. In addition to triggering the sympathetic nervous system, leptin promotes hypertension [43], whereas adipokine accelerates the oxidation of free fatty acids, oxidative stress, and secretion of cytokines [44, 45]. Further, adipose tissue is a known source of pro-inflammatory cytokines, which are secreted systemically within and around the kidney and contribute to an inflammatory state of the kidney. The crosstalk in the adipose-renal axis is crucial for response to kidney injury as well as normal kidney function. Secretions of cytokines, tumor necrosis factor (TNF)-a, interleukin (IL)-6, and interleukin (IL)1β, and other cytokines result in the response of macrophages and other immune cells [46]. Engagement of immune cells may initiate or worsen the inflammatory environment of kidneys, inter-organ, and around, contributing to immune system dysfunction and low-grade inflammation, which later may progress into chronic kidney disease [47].

Furthermore, adipose tissue macrophages significantly produce other inflammatory factors, including cathepsin S, macrophage inhibitory factor, nerve growth factor, and inducible nitric oxide synthase (iNOS) [48, 49]. Noteworthy, other adipose tissue inflammatory factors reactants that potentially are pathogenic in the acute phase of kidney injuries, such as c-reactive protein, plasminogen activator inhibitor 1 (PAI-1), proteins of the complement system, chemotactic adipokines, prostaglandins and reduced anti-inflammatory factors [50, 51, 52, 53]. Ion functional disturbances in the kidney tubule, leading to renal fibrosis, may be due to abnormal inflammatory processes in general but also due to the involvement of plasminogen activator inhibitor 1 (PAI-1), illustrating the complex cascade of the pathogenesis of CKD.

3.3 RAAS activation, insulin resistance, and kidney disease

The renin-angiotensin-aldosterone system (RAAS) is a critical system influenced by the VAT and excess circulating insulin. VAT, whether located in the abdomen cavity or the kidney, in inter-organ, due to endocrine activity, increases intra-renal pressure and RAAS activation [54]. RAAS is inappropriate under conditions of obesity and insulin resistance, and individuals with excess VAT show increased plasma renin activity, angiotensinogen, and circulating aldosterone [55]. The RAAS activation leads to sodium retention in tubules, contributing to systemic and intra-renal hypertension and impacting renal blood flow, perfusion, and intra-glomerular hypertension [56]. Consequently, related stress is imposed on renal vasculature glomerular cells and podocytes, and eventually, there is a decline in kidney function [57]. Alternatively, insulin resistance plays a vital role in kidney damage development. Predominantly, insulin resistance is driven mainly by pro-inflammatory cytokines released principally by VAT. Circulating cytokines affect insulin signaling [58], modulating the glomerular filtration barrier and podocyte function [59]. Animal and in vitro studies documented that insulin increased the glomerular permeability to albumin [60]; in clinical practice, conditions with hyperinsulinemia and hyperglycemia are associated with albuminuria [61]. Also, insulin resistance has been shown to promote the progression of renal fibrosis [62].

3.4 Thyroid, adipose tissue, and kidney disease

The thyroid gland drives metabolic processes in the human body, and hormonal alternations are associated with kidney diseases [63]. Thyroid function, including thyroid function disease, can affect kidney function and progression to CKD. In patients with CKD and end-stage kidney disease, low-free triiodothyronine (fT3) is present, and these patients are prone to hypothyroidism [64]. However, when renal function declines, thyroid hormone alternations occur, and thyroid stimulation hormone (TSH) rises, with or without reduced free thyroxine (fT4) and low fT3 [65]. Interestingly, kidney function improves in patients with thyroid hormone supplementation. The hormonal alternations of the thyroid are traditionally interpreted in the context of kidney dysfunction within the concept of non-thyroid disease. However, the possibility that disturbances may arise due to other pathways or diseases is seldom discussed. Despite sufficient evidence linking thyroid and kidney disease, the causality and directionality of the association still need to be made clear. Also, there is insufficient evidence about impaired thyroid function’s role in patients with preserved or moderated reduced estimated glomerular filtration rate (eGFR) [63]. At the same time, thyroid hormones are determinants of energy expenditure and contribute to regulating appetite and releasing cytokines from adipose tissue, which inform the central nervous system (CNS) on energy storage [66]. In other words, there is a crosstalk between the thyroid and adipose tissue in the human body, and the thyroid drives mechanisms to localize and store adipose tissue [66].

On the contrary, data report that thyroid hormones did not directly cause CKD progression in the general population after 20 years of follow-up [67]. Nevertheless, there is an insufficient understanding of disease or kidney function impairment in the absence of thyroid disorders, and given the crucial role of thyroid hormones on adipose tissue, an under-recognized triangle mechanism may explain this relationship compared to the individual relationship between thyroid and kidney or adipose tissue and kidney only. From a physiological standpoint, kidney function assessment is based on GFR estimation based on serum creatinine and/or cystatin C. The first biomarker is related to thyroid and muscle metabolism. In contrast, the second biomarker, thyroid, has a significant impact on cystatin C [68] levels, which at the same time is released by adipose tissue, suggesting that an underlying biological plausible axis exists between thyroid, adipose tissue, and kidney disease crosstalk mechanism that needs further exploration. Recent animal studies indicated that triiodothyronine (T3) increases the production of cystatin C in adipocytes [22]. Similar findings have been reported from a study in the German population, free of kidney diseases, that VAT has been associated with serum cystatin C and reduced eGFR. In addition, triiodothyronine (T3) has been found to promote adipose tissue hyperplasia and mediate adipocyte proliferation [69]. Tracing further the effect of triiodothyronine (T3) on adipocytes suggests that it influences adipocyte hyperplasia. In contrast, later, the adipocytes, through the release of cytokines, impair the conversion of thyroxine (fT4) into triiodothyronine (T3).

4. Conclusion

Summarizing this chapter, a cascade of changes and mechanisms involved in interactions of adipose tissue and kidney function, we discussed the basis of this inter-organ crosstalk, which includes adipose tissue storage, inflammation RAAS activation, and insulin sensitivity. However, characterizing further fundamental cellular changes at the level of adipocytes and affected changes of the microenvironment of adipocytes through the influence of thyroid function builds the new mechanistic infrastructure of inter-organ crosstalk between three key players: thyroid, adipose tissue, and kidney. Further elaboration of serum cystatin C levels may help identify relevant pathways to new axis thyroid-adipose tissue-kidney dysfunction into progression to kidney disease (Figure 1).

Figure 1.

Crosstalk between adipose tissue and kidney function, physiology (panel A) and pathophysiological mechanisms (panel B).

Conflict of interest

The authors declare no conflict of interest.

Author contributions

All authors contributed equally to this chapter. Conceptualization, V.B.M, B.M, writing—original draft preparation, V.B.M, B.M; writing—review and editing, V.B.M, B.M; visualization, V.B.M, B.M. All authors have read and agreed to the published version of the chapter.