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Role of Obesity and Mediators of Adipose Tissue in Renal Transplant and Disease

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Submitted:

29 December 2023

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03 January 2024

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Abstract
This review provides insight into the role that obesity, but especially mediators of the adipose tissue, have in both renal disease and transplantation. In particular, we focus on the functions of leptin and adiponectin, inflammatory mediators with widely known clinical implications, as well as on the role of arachidonic acid-derived eicosanoid metabolites. These latter compounds, epoxyeicosatrienoic (EETs) and hydroxyeicosatetraenoic (HETEs) acids, which modulate the liberation of cytokines in the adipose tissue, are generated in the epoxygenase pathway of arachidonic biotransformation via CYP450 enzymes. There is accumulating evidence suggesting that EETs and HETEs may have a critical role in the onset and outcome of chronic kidney disease and renal transplantation. Finally, we also discuss the reported effect that the presence of genetic variants in leptin, adiponectin, EETs and HETEs-related genes may cause in renal patients and recipients. The levels of cytokines of the adipose tissue and related compounds play a remarkable role in both renal disease and transplant. Accordingly, novel therapeutic strategies are being developed based on the modulation of their concentrations in patients with various diseases.
Keywords: 
Subject: Medicine and Pharmacology  -   Urology and Nephrology
Chronic kidney disease (CKD) is a global health problem whose incidence is around 8-16% (1). It consists of damage at the renal level that is usually characterized by a significant decrease in glomerular filtration rate (GFR), below 60 mL/min/1.73 m2, for more than three months (2). Among the susceptibility factors that increase the possibility of kidney damage, we can find advanced age, obesity, diabetes or arterial hypertension. Factors that initiate renal damage include autoimmune diseases, diabetes or systemic infections, whilst factors that worsen renal damage and accelerate renal function deterioration include smoking, dyslipidemia or obesity (3). The most advanced manifestation of chronic kidney disease is end-stage kidney disease (ESKD). Once this stage of the disease has been reached, the need to initiate renal replacement therapy for renal function by means of dialysis or renal transplantation is considered, the latter being the treatment of choice, even though it is not free of short- and long-term complications.
There is a myriad of mediators of kidney damage and post-transplant complications. The objective of this review was specifically to present information supporting the concept that adipose tissue mediators, mainly adiponectin and leptin and related substances such as eicosanoids derived from arachidonic acid, can also have an important role in the genesis and/or aggravation of kidney disease, as well as being associated with the clinical evolution of the graft after kidney transplantation.

Obesity in Chronic Kidney Disease

Obesity has been identified for years as a major cause of kidney disease, including CKD (4-6), with evidence of causality in several studies (4,7-10). Directly, obesity can lead to structural and inflammatory changes at the renal level (11), whilst it can indirectly influence the onset and worsening of diabetes mellitus (12). Obesity-related kidney injury may present a circulatory component, either by injury to blood vessels or compression by adipose tissue (13); an inflammatory component, by activation of inflammatory cytokines (14); or a hormonal component, through the effect on the renin-angiotensin system (15). In addition, obesity may produce metabolic and biochemical alterations that predispose to kidney disease, even in the presence of normal renal function (6,16).
Overweight and obesity are considered important risk factors for the onset of CKD, largely due to their close relationship with hypertension, diabetes mellitus (17) and cardiovascular risk (18), thus predisposing to pathologies such as diabetic nephropathy, hypertensive nephrosclerosis or focal and segmental glomerulosclerosis (6,7). However, the pathogenic mechanisms involved in the association of obesity with kidney disease are not yet fully elucidated (19). From a pathophysiological point of view, obesity triggers an increase in tubular sodium reabsorption, with altered natriuresis and consequent volume expansion due to activation of the sympathetic nervous system and the renin-angiotensin-aldosterone axis (17). From this point on, a series of pathophysiological mechanisms occur that trigger the development of arterial hypertension (HT), with increased renal flow and glomerular filtration rate. This increase in glomerular filtration rate, together with other metabolic alterations such as insulin resistance and diabetes mellitus, eventually lead to renal damage (4,6,7). The accumulation of adipose tissue in obesity, especially in the abdominal region, causes renal compression, and consequently an increase in intrarenal pressure, which leads to a reduction in tubular flow and subsequent increases in sodium reabsorption (4,6,7). In addition, obesity is associated with inflammation, which increases the production of inflammatory cytokines, being in itself a risk factor for the loss of renal function (20,21).

Reverse Epidemiology of Renal Transplantation

The concept of reverse epidemiology was born a few years ago, posing as an anodyne situation whose cause is still unknown, mainly present in the context of heart failure or hemodialysis, and which forces us to rethink certain medical axioms related to obesity. In view of this, it is inevitable to wonder whether renal transplant patients also present this phenomenon. Contrary to what happens in hemodialysis, the study of the effect of obesity in renal transplantation is controversial (22). On the one hand, a BMI > 30 kg/m2 has been identified as the most important risk factor for surgical wound infection in the renal transplant recipient (23), with consequent complications for both graft and patient. The relationship between a high BMI and a significant increase in surgical time and postoperative stay has also been described (24), as well as a higher incidence of early graft loss caused by vascular complications, such as renal artery thrombosis (25). Therefore, it seems logical to associate a poor post-transplant prognosis with obesity. However, on the other hand, in a meta-analysis conducted by Nicoletto et al. on the effects of obesity on the development of renal transplantation, the researchers conclude that the relationship between obesity and renal graft loss, death from cardiovascular causes or from any cause, differs according to the era of the study, such that in studies prior to the year 2000, obesity was a risk factor for the appearance of these variables, while in those after this year, obesity did not seem to influence them (22). There is another issue, pretansplant obesity, that makes the relationship between obesity and renal transplantation even more complex. Post-transplant obesity goes hand in hand with metabolic disorders such as HT, dyslipidemia or DM (26), classically associated with obesity. However, it has been paradoxically observed that a high BMI is associated with better survival in hemodialysis patients, including those on the list for renal transplantation (27-30). Since a large percentage of transplant patients come from hemodialysis, the effect of obesity in hemodialysis patients who are going to undergo renal transplantation would not be well established (31). According to the results of the meta-analysis performed by Ahmadi and co-workers (32), extreme pre-transplant BMI figures in adults are associated with an increase in transplant patient mortality and graft failure, and no paradoxical obesity effect was observed in their population. The authors argue that the paradoxical effect observed in hemodialysis patients who are candidates for kidney transplantation could be due to the contrast between the short- and long-term consequences of obesity, i.e., while obesity increases long-term cardiovascular mortality, it could at the same time attenuate short-term mortality associated with malnutrition, inflammation and protein energy wasting syndrome (33). A return to normal phenomenon, which would be in place after renal transplantation (33), has also been proposed.
The question thus arises regarding the recommendation of weight loss prior to transplantation. As previously discussed, there are several studies evidencing the negative effect of obesity on graft and renal transplant recipient (34). A calculator has even been developed that evaluates graft survival including BMI among its variables (35). This is why several authors recommend weight loss in potential renal transplant recipients (35,36), while other authors consider that BMI interventions should not be performed in patients on the transplant list, given the observed benefit of obesity on hemodialysis patients (32).

Adipose Tissue

Until a few years ago, adipose tissue was considered only a passive energy storage site. However, after the discovery of leptin, a protein secreted by adipose tissue, this concept changed, and it is now considered an active endocrine organ, secreting numerous adipokines, cytokines, growth factors and exosomal microRNAs with important systemic functions (37,38). Likewise, adipose tissue has a prominent role in the regulation of energy metabolism (39) and lipid homeostasis (40). It is now also known that adipose tissue is distributed diffusely throughout the body, varying the endocrine and metabolic functions it performs depending on its location (39).
There is increasing evidence of the involvement of adipose tissue in the physiology and pathophysiology of multiple diseases (41). Histologically, the adipose tissue is composed of two distinct types of elements, adipocytes and interadipocyte-vascular stroma, consisting of extracellular matrix with scattered fibroblasts, preadipocytes (immature adipocyte precursors), endothelial cells and immune cells (42,43). The presence of immune system cells in adipose tissue is not surprising if we consider the chronological evolution of the organs that comprise it. Inflammation, framed in the context of the immune response, consists of a series of humoral and cellular reactions aimed at defending the organism from aggressions, including infection and tissue damage, finally reaching the restoration of the functional and morphological integrity of the affected tissues (44,45). In this context, obesity is considered a state of chronic low-grade inflammation, characterized by an increase in proinflammatory markers, without obvious clinical signs, which is why it has been termed a subclinical inflammatory state (34). Even though this situation might seem to be a reaction of the organism of lesser intensity than that activated in the face of an acute aggression, it could also represent the ideal environment for the larval development of various diseases of later onset.
In a normal situation, the cells of the immune system residing in the adipose tissue actively participate in the maintenance of this tissue, eliminating detritus or apoptotic cells, and maintaining the homeostatic balance (46); however, in a situation of chronic inflammation as obesity represents, the existing balance can be altered. Adipose tissue undergoes marked hypertrophy and hyperplasia in response to an insult, leading to hypoxia, dysregulation of adipokines and, consequently, low-grade inflammation characterized by increased infiltration and activation of innate and adaptive immunity of immune cells (47). Chronic excess food intake leads to pathological expansion of adipose tissue, with hypertrophic adipocytes that fail to store energy, resulting in dysfunction, dyslipidemia and insulin resistance (48). This altered, inflamed, adipose tissue causes the release of various proinflammatory factors from adipocytes, thus amplifying the inflammatory situation (48). There are many questions about the in-situ activation of these inflammatory cells. It is now known that obesity leads to a qualitative alteration of the resident macrophages in adipose tissue, as well as the generation of oxygen free radicals, all of which leads to insulin resistance (49). The body tends to maintain the equilibrium situation at all times, so this inflammatory reaction of the adipose tissue may be necessary to maintain the homeostasis in the rest of the body. Moreover, the changes carried out in the adipose tissue also occur in other organs of the body, such as the liver, pancreas or muscle tissue, which gives us an idea of the universal nature of the metabolic dysfunction that takes place in the context of obesity (50).
Renal transplantation is a real challenge for the balance of the immune system, making the nephrologist to keep a challenging balance between the complex mechanism perfected over the years that allows us to survive pathological processes, and to avoid rejection of an organ understood by the organism as foreign. The immune system is the fundamental axis around which transplantation revolves and there are continuous advances in this field, controlling the body’s immune response by means of immunosuppression. As a fundamental organ of the immune system, adipose tissue plays an important role in this balance, interrelating the rest of the organs through inflammatory mediators.

Inflammatory Mediators of Adipose Tissue

Leptin

Leptin is a 16 kDa protein with 167 amino acids (51) that belongs to the interleukin-6 family, a group of inflammatory cytokines (52,53). Associated since its inception with adipose tissue, numerous pleiotropic effects of this protein are now known (54). Blood leptin concentrations follow a pulsatile and circadian pattern, with lower levels from early to mid-afternoon and higher levels between midnight and early morning (55). Leptin concentrations are influenced by factors such as sex, hormones or drugs. Thus, glucocorticoids increase leptin levels, as do insulin or estrogens (56), while fasting, metabolic acidosis, androgens, cold or beta-adrenergic agonists inhibit its production (57,58). Leptin values are higher in overweight and obese individuals (59), and also in women compared with men, after adjusting for BMI (60). This sexual dimorphism, independent of BMI, is attributed to differences in fat mass, body fat distribution and sex hormones (61).

Leptin in CKD

There is some controversy surrounding the relationship of leptin levels in CKD patients. Leptin is filtered in the renal glomerulus and catabolized in the renal tubules (62) via megalin (63). It has been observed how leptin levels are elevated in patients with moderate CKD (64-67), presumably due to lack of renal clearance of the protein (57,68). However, there may be other pathophysiological mechanisms contributing to this phenomenon. For instance, hyperleptinemia in patients with CKD could be produced by an increase in the production of this protein by the adipocytes of these patients. Thus, in two different studies, the authors demonstrated that adipocytes in a uremic environment produced overproduction of leptin (69,70). In addition, factors such as increased fat mass, hyperinsulinemia or inflammation (54), could contribute to the higher figures observed in patients with CKD. In this line, several studies have evidenced the relationship between this adipokine and renal damage, presumably through its participation in the development and progression of vascular damage, increased collagen production and increased mesangial cellularity (71-73). In addition, taking into account the close relationship between leptin and the immune system, and considering that CKD is characterized by a chronic inflammatory state, several in vitro studies have evidenced how leptin secretion was regulated by proinflammatory cytokines such as TNF-α (69,74,75) or IL-6 (67), resulting in higher levels in these individuals. In contrast, Silva et al. observed that leptin levels in patients with CKD and normal BMI were similar to those of healthy subjects, but lower than those of overweight or obese patients (76), which attributes the effect on leptin levels to the impact of BMI rather than to CKD (76). Likewise, another study showed that plasma leptin levels were similar in HD patients and healthy subjects with the same BMI (BMI of 25.0 ± 4.2 kg/m2) (77). All this suggests that the hyperleptinemia that accompanies CKD has a complex and multifactorial origin, including a possible increase in leptin production by the adipose tissue of these patients, a consequence of decreased renal clearance, or the hyperinsulinemia and the inflammatory state present in many renal patients (54).

Leptin in Renal Transplant

With regard to renal transplant, leptin levels are elevated in ESKD, drop dramatically after grafting (78) but increase again with time after transplant (79,80), reaching similar levels to the pre-transplantation period in a few years (81). The possible relationship of leptin with the elevated cardiovascular risk in renal transplant recipients is very interesting. As it is known, the main cause of death in these patients is cardiovascular disease, and leptin, which increases its levels post-transplantation, is a peptide closely related to hypertension and arteriosclerosis. In addition, the germ of cardiovascular risk is calcification and vascular stiffness, whose manifestations throughout the body will mark the evolution of a transplant patient. In this regard, Lee et al. have shown that leptin levels presented a clear correlation with peripheral vessel stiffness in renal transplant recipients (45), indicating a putative implication of leptin in the evolution and cardiovascular events of renal transplant patients. In the same manner, an association could be established, from the endothelial point of view, between leptin and delayed graft function (DGF), given the inflammatory effects associated with leptin and knowing its relationship with vascular proliferation in the glomerulus, vascular damage, increased collagen and cell hypertrophy (71,72). In short, leptin has a proinflammatory action, with a close relationship with angiogenesis and hematopoiesis, which could explain its importance in the innate and adaptive immunity so relevant in renal transplantation (82,83).

Implications of Genetic Variability in Leptin Genes

Among the genes in the leptin pathway, the one encoding its receptor, LEPR (ENSG00000116678, HGNC:6554), has attracted most of the attention. It consists of 24 exons and is located on chromosome 1 between positions 65,420,652 and 65,641,559 (84). In recent years, it has been observed that single nucleotide polymorphisms (SNPs) in the LEPR gene encoding the protein receptor could influence susceptibility to certain pathologies, such as obesity (85), diabetes mellitus (86), hypertension (87) or cardiovascular mortality (88). However, in the field of renal transplantation, published articles are scarce. One study demonstrated the influence of the LEPR Gln223Arg variant on the development of post-transplant Diabetes mellitus (PTDM) (89), which has been confirmed in a later work by our group that analyzed more SNPs in this gene locus (86). In addition, renal recipients who were carriers of the SNP rs1805094 showed longer graft survival than non-carriers did (90). Furthermore, three SNPs in the LEPR gene, namely rs1137101, rs1805094 and rs1137100 have been associated with delayed graft function, acute rejection and renal function one year post-transplant in renal recipients (91).
The mechanism by which variants in the LEPR gene might translate into clinical events is unknown. Daghestani et al. (92) observed how carriers of the rs1137101 SNP presented higher leptin levels, but this association was only described in women with obesity. In other studies, this association between LEPR SNPs and leptin levels has not been confirmed (93,94). A different explanation for clinical repercussions of these genetic variants would be that the effect on the leptin receptor might alter the subsequent intracellular metabolic cascade that occurs after its activation.

Adiponectin

Adiponectin, a 30-kDa protein linked since its discovery to adipose tissue, has subsequently been found to be also produced, in smaller quantities, from cardiac myocytes and skeletal muscle cells (95,96). In plasma, adiponectin can be found in various multimeric forms: globular adiponectin, full-length and low (LMW), medium and high molecular weight (HMW) adiponectin (97). The HMW multimer appears to be the most active form of adiponectin, with the plasma concentration of the HMR multimer being related to insulin sensitivity, so that a failure in multimerization is associated with type 2 diabetes mellitus (98).

Adiponectin in CKD

The main route of elimination of adiponectin is hepatic and, secondarily, the renal route (99). Thus, it has been observed how adiponectin monomers and dimers are small enough to cross the glomerular filtration barrier, so these substances are identified in urine; however, the HMW multimer has also been observed to be excreted in the urine of patients with proteinuria, which may reflect a defect in the filtration barrier (100). The relationship between adiponectin and the kidney rise numerous questions. In patients diagnosed with CKD, adiponectin values could be related to the progression of kidney disease, even reaching ESKD, as evidenced by several studies (101-103). However, the specific reason is not well established. Even though in CKD there is increased resistance to insulin action (104), higher risk of cardiovascular disease and dyslipidemia (105), paradoxically, adiponectin levels are elevated in this situation. It would be logical to attribute this to the decline in renal function. However, other factors could be related, namely a possible malfunction of adiponectin receptors leading to resistance to the action of the protein, or an increase in its production, secondary to a state of generalized inflammation of the organism (105). The increase in plasma adiponectin levels observed in CKD is accompanied by an increase in adiponectin protein and mRNA expression in subcutaneous and visceral adipose tissue, suggesting that there is a stimulus that produces an increase in adiponectin, despite elevated plasma levels (105). In parallel, it has been shown that in the muscle tissue of patients with CKD, the expression of adiponectin receptors increase (106), suggesting that uremia could confer resistance to adiponectin (107). In any case, and similar to the case of leptin, the relationship between adiponectin and renal function is not yet fully understood.

Adiponectin in Renal Transplant

There are very few studies on adiponectin carried out in renal transplant recipients, where the restoration of renal function does not necessarily imply a return to a better cardiovascular situation. Chudek et al. showed that pre-transplant adiponectin levels were significantly higher than those of healthy subjects. After the transplant, concentrations decreased but did not reach the levels seen in the control population (108). Moreover, Idorn et al. have argued that, despite the decrease in protein levels, its relationship with various cardiovascular and metabolic variables will not be reestablished until several months after transplantation, with a period of clinical and metabolic instability (109). It is again worth asking whether the persistence of high adiponectin concentrations is due to a larval inflammatory state, or perhaps to the existence of alterations in the metabolic cascades triggered at the intra- and extracellular level by adiponectin (110). In relation to the high cardiovascular risk of this population group, one could also wonder whether patients with higher adiponectin levels post-transplantation are also those with better cardiovascular profile and longer survival. According to a study, renal recipients with lower baseline adiponectin levels also had a worse metabolic profile, with lower HDL cholesterol levels, higher CRP (C-Reactive Protein) levels, total cholesterol and higher BMI. In contrast, patients with higher levels had worse survival, similar to what happens in CKD (111). Based on the above, it is evident that the relationship between adiponectin and renal transplantation is complex. The levels of this hormone decrease after grafting, which evidences the restoration of certain metabolic feed-back and, perhaps, a decrease in the inflammatory state of the individual. Conversely, the figures remain higher than in the general population. To make matters more complicated, and similar to what is observed in hemodialysis, patients with higher levels present worse survival instead of the expected better cardiovascular and metabolic profile. In this complex relationship, it is worth highlighting the possible impact of various post-transplant events, such as weight gain, improved renal function, the use of drugs that alter the lipid profile, diabetes or the use of immunosuppressants (109).
Regarding to post-transplant graft evolution, a study showed that rejection was observed more rapidly in heart transplanted mice which were deficient in adiponectin than in healthy mice (112), which could indicate a lower T-cell response in the presence of adiponectin (113). Furthermore, adiponectin-deficient heart transplanted mice show more incidence of ischemia-reperfusion, myocardial infarction and myocardial apoptosis rate (114).

Implications of Genetic Variability in Adiponectin Genes

The adiponectin, ADIPOQ, gene (ENSG00000181092, HGNC:13633), consists of three exons and is located on chromosome 3 between positions 186,842,704 and 186,858,463.
Several genetic variants have been described linked to the plasma levels of this adipokine, which directly or indirectly play an important role in the susceptibility to certain pathologies such as obesity (115), insulin resistance, type 2 diabetes mellitus (116) or metabolic syndrome (117). With regard to renal transplantation, there is a marked paucity of data. Only Kang et al., who studied the association of PTDM with eight polymorphisms in ADIPOQ and also in the gene receptor ADIPOR1 in a sample of 575 renal transplant recipients, obtained an association between PTDM and the homozygous ADIPOQ rs1501299 TT genotype in males carriers (118). Our group studied the influence of ADIPOQ SNPs on graft survival and found that carriers of the rs1501299 variant showed worse survival compared to non-carriers (90).

Arachidonic-Derived Vasoactive Eicosanoids

The secretion of leptin and adiponectin in the adipose tissue is affected by the eicosanoid metabolites of arachidonic acid. Heme oxygenases are responsible for maintaining normal metabolic cellular functions and the production of potent antioxidant and anti-inflammatory molecules (119,120). In turn, the expression of these enzymes is up-regulated by arachidonic-derived epoxyeicosatrienoic acids (EETs). Burgess et al. (121,122) have reported that EETs levels have a direct influence on the regulation of adipogenesis and adipocyte function, by decreasing the production of circulating inflammatory cytokines, e.g. leptin, while increasing adiponectin levels (Figure 1). Indeed, Dai et al. have described the beneficial properties of these metabolites in inflammatory diseases related with obesity (123).
Arachidonic acid (AA) main function is to work as a precursor of proinflammatory bioactive mediators in at least three known metabolic pathways related to the onset, development, and regression of renal inflammation (Figure 2).
First, the cyclooxygenase (COX) pathway, through which AA is metabolized to prostaglandins and thromboxanes; second, the lipooxygenase (LOX) pathway, which leads to the formation of leukotrienes and lipoxins, and the third pathway, the epoxygenase pathway, in which cytochrome P450 (CYP450)-mediated metabolism produce different vasoactive eicosanoids, namely EETs and hydroxyeicosatetraenoic acids (HETEs) (124). The latter is the main pathway of AA metabolism in the kidney (125,126).
Several isomers of EETs are produced by this epoxygenase metabolic route, being CYP2 is the main CYP450 involved (124). These metabolites are very rapidly metabolized by the soluble epoxide hydrolase (sEH) enzyme, encoded by the EPHX2 gene, to dihydroxyeicosatrienoic acids (DHETs), with considerably weaker biological activity (127). In addition, a number of HETE isomers are also formed, of which 20-HETE is the main product and whose formation in the human kidney is mediated by CYP4F2 and CYP4A11 (124).

Eicosanoids in CKD

Renal physiological function is clearly influenced by both the vascular and tubular actions of these AA-derived metabolites, which contribute to the kidney’s ability to maintain electrolyte and body fluid homeostasis. Among other functions, EETs stand out for their renoprotective role. A decrease in the concentration of EETs can significantly influence the occurrence of vascular and tubular abnormalities of renovascular disease (128). These eicosanoids protect the kidney against inflammatory processes and renal injury by helping to increase renal blood flow, GFR and sodium excretion. Thus, EET analogs lower blood pressure, decrease kidney inflammation, improve vascular endothelial function, and decrease kidney fibrosis and apoptosis (129).
On the other hand, HETEs, especially 20-HETE, are vasoconstrictor metabolites implicated in the development of acute and chronic kidney disease, as well as polycystic kidney disease, in addition to increasing renal cell vasoconstriction and inducing hypertension (130). Likewise, they stimulate renal tubular cell hypertrophy and podocyte destruction. These effects have been confirmed by using 20-HETE antagonists, whose function was protective, reducing vascular inflammation, tubular injury, and loss of renal function (131).

Eicosanoids in Renal Transplant

Chronic graft nephropathy represents the major cause of long-term dysfunction in renal transplantation (132-134), which is determined by ischemia-reperfusion events, innate and adaptive immune response and the effect of drugs such as anticalcineurinics, which produce endothelial dysfunction (135-137). These factors, along with the fact that cardiovascular disease continues to be one of the leading causes of graft loss (138) and that the AA-epoxygenase pathway is key in the cardiovascular function, have led to an increase in the number of studies on the link between this route and renal transplantation. Indeed, Duflot et al. have highlighted the importance of preserving the bioavailability of EETs for their short- and long-term benefits in renal transplantation (139). There is also available literature on the role of HETEs in renal transplant outcomes. Dołegowska et al. showed that the dynamics of 20-HETE changes, which occurs during early phase of allograft reperfusion, is associated with early post-transplant graft function. The authors regarded 20-HETE as a novel clinical marker of post-transplant allograft function (140).

Implications of Genetic Variability in Eicosanoid Genes

The most important genes involved in the metabolism of AA to EETs are CYP2J2 and CYP2C8., with two widely studied variants, CYP2C8*3 R139K/K399R (rs10509681) and CYP2J2*7 G-50T (rs890293), strongly related to decreased enzymatic activity or lower transcription rate (141,142). In particular CYP2C8*3 appears to be associated with altered metabolism of CYP2C8 substrates (143,144), and CYP2J2*7 causes a loss of the Sp1 transcription factor binding site resulting in decreased expression of the enzyme (145). Interestingly, these SNPs have shown to produce a significant decrease in EETs levels (146-148).
CYP2C8*3 has been observed mostly in Caucasian population and has been associated with an increased risk of delayed renal function and reduced creatinine clearance in renal transplant recipients (149) as well as with increased susceptibility of diabetic kidney disease (150). As for CYP2J2*7, considering that the enzyme synthesizes renoprotective EETs, carriers could present a decrease in this protective activity. In addition, a lower transcription rate of CYP2J2 caused by the SNP could contribute to arterial hypertension because of the reduced levels of vasodilator EETs (147). Indeed, we studied the effect of this variant on cardiovascular event-free survival after kidney transplantation and reported a significantly lower survival for carriers of the CYP2J2*7 allele.
The EPHX2 gene, coding for the enzyme responsible for EETs degradation, can also present different SNPs that have been associated with enzymatic and kinetic activity, being the most relevant EPHX2 3’UTR A>G (rs1042032), R287Q (rs751141) and K55R (rs41507953) (151). The GG genotype of the EPHX2 3’UTR A>G variant has been related to lower GFR and higher serum creatine values in renal transplant recipients as well as with an increased risk of acute rejection and worse graft function. In this case, both the donor’s and the recipient’s genotype showed this association with rejection (152). In contrast, Lee et al. reported an increased risk of graft dysfunction for the AA genotype (153). EPHX2 R287Q results in decreased sEH activity and has been associated with coronary artery calcification (153) and hypertension (154). Finally, carriers of the EPHX2 K55R show increased sEH activity and therefore higher EETs degradation (155). The variant produces a decreased endothelium-dependent vasodilation, which in turn implies reduced blood flow (151).
The formation of 20-HETE, the most relevant HETE, is mediated by the CYP4F2 and CYP4A11 genes. Initially, the CYP4F2 V433M (rs2108622) polymorphism was reported to reduce the production of 20-HETE by 50% (156). However, subsequent studies suggest this SNP to be associated with increased urinary excretion of 20-HETE (157,158). We have analyzed associations of the CYP4F2 V433M SNP with the risk of diabetic kidney disease and with clinical outcomes in these patients. We observed that carriers of the 433M variant allele had lower risk of diabetic kidney disease, in addition to lower urinary 20-HETE levels. We hypothesized that 433M carriers would produce less 20-HETE, resulting in reduced vasoconstrictor activity in kidney tissue. In turn, this would alleviate glomerular capillary pressure causing the observed reduction in filtration (150).
In renal transplantation, the V433M polymorphism has been related to acute rejection, delayed graft function (159) and PTDM (160). With regard to CYP4A11, the F434S substitution has been shown to lead to a decrease in enzymatic activity and has been related to hypertension and increased vasoconstriction (161,162). Consistent with these findings, renal recipients whose donors carried the CYP4A11 434S variant showed impaired creatinine clearance compared to wild-type carriers (163).

Perspectives and Conclusions

In this review, we have focused on the role that obesity can play in CKD and in the clinical evolution of renal transplant. In particular, we have discussed in depth the mediators of the adipose tissue, which are gaining increasing attention as significant actors in processes leading to renal injury as well as in renoprotective mechanisms.
Experimental and clinical evidence implicates the two major adipose tissue cytokines, adiponectin and leptin, in renal damage. There is a growing body of evidence indicating various potential therapeutic strategies based on this. For instance, the development of leptin signaling modulators, namely peptide-based receptor antagonists, leptin mutants, antibodies, and nanobodies (164) represents a promising strategy for the treatment of diseases where leptin is involved. Indeed, a very recent study shows in an animal model of renal ischemia how local, intrarenal postischemic treatment at reperfusion with a leptin antagonist prevented apoptosis and inflammation and was renoprotective (165). In the same line, leptin antagonists have also been shown to ameliorate CKD-associated cachexia in mice (166). Common drugs have also been used to antagonize leptin damaging effects. For instance, a clinical trial showed how treatment with lovastatin can reduce leptin serum levels in patients with type 2 diabetic nephropathy (167).
Moreover, leptin and adiponectin, being as they are associated with cardiovascular disease, have also been proposed to be used as a combined biomarker (leptin-to-adiponectin ratio) of adverse events in patients on kidney replacement therapy (168). Nevertheless, it should be mentioned that information regarding adiponectin in chronic kidney disease (CKD) is not consistently uniform, likely owing to its intricate and varied actions. Moreover, the existence of various adiponectin isoforms, each with distinct roles, the initiation of diverse signaling pathways, and the varied expression of its receptors in different tissues, could further contribute to the controversial nature of the data (169). In any case, it has been proposed that enhancing the synthesis of adiponectin in CKD patients may have therapeutic potential, as inferred from the results of studies on rodent models of CKD, where adiponectin administration was able to attenuate kidney injury and fibrosis (170). For instance, PPAR agonist tesaglitazar has shown promising results in clinical trials for the treatment of type-2 diabetes trough increasing adiponectin circulating concentrations (171).
As previously explained, inhibiting soluble epoxide hydrolase (sEH) proves effective in maintaining endogenous epoxyeicosatrienoic acids (EETs) levels while reducing dihydroxyeicosatrienoic acids (DHETs) levels. This has therapeutic potential for cardiovascular, central nervous system, and metabolic diseases (172). Consequently, the development of sEH inhibitors has been a prominent research focus since the early 21st century. Indeed, sEH inhibitors have demonstrated a protective role in animal models of renal damage and experimental arterial hypertension (173,174). Moreover, mice deficient in sEH exhibit decreased blood pressure, attenuated renal inflammation, and reduced glomerular injury (175). Among the different sEH inhibitors, urea-based compounds are particularly notable due to their general high selectivity for sEH. Various potent sEH inhibitors, whether synthesized chemically or isolated from natural sources, include compounds like AR9281, EC5026, or GSK2256294. These are currently undergoing clinical trials to address conditions such as heart failure, insulin resistance, glucose intolerance, hypertension, endothelial dysfunction, and pain (176).
Additionally, combining sEH inhibitors with other agents, such as COX-2 inhibitors like celecoxib, has proven to enhance efficiency in reducing pain and hypotension (177), which has led to the development of sEH/COX2 dual inhibitors (178). Having said that, further research in areas like CKD is necessary to fully understand the clinical applications of these promising compounds in the future.
In addition to the therapeutic possibilities that targeting these mediators open for renal patients, we should not underestimate the role of genetics. Whilst genetic-based therapies are still far from being developed in this field, there are numerous studies indicating that genetic variants may regulate the levels of adiponectin, leptin, EETs and HETEs, and hence hold the potential to be clinically relevant in the renal setting (150,179,180).
Chronic kidney disease is expected to be one of the global leading causes of death by 2040, and the need for new biomarkers of early diagnosis and progression to ESKD has been repeatedly stressed. In the same manner, renal transplant recipients might benefit from novel markers of clinical outcomes, particularly cardiovascular-related, as this is the main cause of death in this population. These mediators of the adipose tissue, together with the arachidonic metabolites that regulate their secretion, hold the potential to be useful clinical tools in this context.

Funding

This research was funded by grant PI22/00181 and RD21/0005/0031 from Instituto de Salud Carlos III, Madrid (Spain), financed by the European Union – NextGeneration UE, Recovery and Resilience Mechanism, and grant GR21026 from Junta de Extremadura, Mérida (Spain) and Fondo Europeo de Desarrollo Regional (FEDER) “Una manera de hacer Europa”. Funding sources did not have any involvement in the study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication..

Conflicts of Interest

All authors declare that they have no conflict of interest.

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Figure 1. Interaction between arachidonic-acid derived epoxyeicosatrienoic acids (EETs) and cytokines secretion.
Figure 1. Interaction between arachidonic-acid derived epoxyeicosatrienoic acids (EETs) and cytokines secretion.
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Figure 2. Arachidonic acid metabolism pathways.
Figure 2. Arachidonic acid metabolism pathways.
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