Role of Leptin in Chronic Kidney Disease: Comparison
Please note this is a comparison between Version 1 by Susana Coimbra and Version 2 by Catherine Yang.

Leptin is a 16 kDa globular protein that comprises 167 amino acids and presents a tertiary structure. It is mainly produced by adipocytes, and its levels are proportional to fat mass. In blood, leptin circulates in free and protein-bound forms; biologically active leptin exists in the free form. Leptin is cleared from circulation by the kidneys through glomerular filtration and metabolic degradation in renal tubules. Hyperleptinemia has direct and indirect negative effects on renal function. Development of cardiovascular disease (CVD), thickening of the basement membrane of the proximal tubular cells (which increase protein leakage into filtrate) and the activation of protein synthesis (which favors fibrosis and glomerulosclerosis), of NADPH oxidase (which increases reactive oxygen species production and, consequently, inflammation), of the sympathetic nervous system in the kidneys and of the renin–angiotensin–aldosterone system (associated with sodium retention, predisposing it to high blood pressure) are some potential mechanisms proposed to explain the damaging effect of hyperleptinemia on renal function.

  • adiponectin
  • leptin
  • chronic kidney disease
  • cardiovascular disease
  • inflammation

1. Inflammation and Leptin

Inflammation, a hallmark of chronic kidney disease (CKD), is frequently associated with hyperleptinemia once,  proinflammatory cytokines stimulate leptin production.
Visceral adipocytes exposed to the uremic plasma of end-stage renal disease (ESRD)  patients presented an enhanced release of leptin that was linked to an avid uptake of TNF-α by the adipocytes, emphasizing the role of tumor necrosis factor (TNF-α) in the production and release of leptin in ESRD [1][83]. Leptin, and the leptin/adiponectin ratio, correlated positively with TNF-related apoptosis-inducing ligands, known to induce apoptosis, although it can also activate antiapoptotic signals [2][84].
In CKD patients, leptin, interleukin-6, TNF-α and adiponectin are significantly increased, and increase with CKD severity [2][84]. Leptin has also been positively correlated with C-reactive protein in CKD, increasing both with progression of the disease [3][85].
By inducing the production of proinflammatory mediators and reactive oxygen species [4][5][6][86,87,88], leptin may also contribute to the inflammatory process found in renal disease and, thereby, to CVD complications.

2. CVD Risk and Leptin

2.1. BMI (Body Mass Index)

A high BMI is one of the strongest risk factors for new-onset CKD [7][89]. Obesity seems to affect the kidneys via the endocrine activity of the adipose tissue, with increased production of adipokines, such as leptin.
Metabolic syndrome refers to the coexistence of obesity, insulin resistance, atherogenic dyslipidemia and hypertension. In children at stages 2–4 of CKD, leptin was found to correlate positively with BMI and triglyceride levels, and negatively with high-density lipoprotein cholesterol (HDLc)  and insulin resistance [8][90]. It has been suggested that in ESRD patients, high leptin concentrations might be a consequence of metabolic syndrome, which is highly prevalent in ESRD [9][91]. A study by Tsai et al. of hemodialysis patients showed that fasting leptin correlated positively with metabolic syndrome, and that pre-hemodialysis body weight was a possible influencer of leptin levels in these patients [10][92]. It was also reported that the predictive value of leptin for all-cause and CV death seems to be dependent on waist circumference [11][93], one of the criteria used to define metabolic syndrome. According to theour data, patients on dialysis with diabetes mellitus and patients with both diabetes mellitus and hypertension had higher leptin levels than those without diabetes mellitus or hypertension, or only with hypertension [12][9]. Controversially, others have reported no significant associations between leptin or the leptin/BMI ratio and all-cause and CVD-related mortality in patients on hemodialysis [13][94].
On the other hand, dialysis patients with a higher BMI showed better nutritional status compared to normal or overweight subjects [14][95], suggesting a role for fat in nutritional status. It was reported that, in dialysis patients, subcutaneous fat may be an indicator of nutritional status, while visceral fat is probably an indicator of inflammation [15][96]. Non-obese patients under hemodialysis with elevated leptin concentrations also presented a good nutritional status [16][97], suggesting that high BMI may not influence nutritional status.
ESRD is frequently associated with anorexia, malnutrition and hypervolemia, a setting that seems to correlate with leptin levels. In dialysis patients, leptin was independently associated with protein energy wasting and, consequently, with poor prognosis [17][29]. In a study conducted on hemodialysis subjects, the deceased patients presented lower leptin values, which were associated with hypervolemia and malnutrition [18][98]. In patients under dialysis, hypervolemic subjects presented lower leptin values and poorer nutritional status than normovolemic patients [19][99]; overhydrated dialysis patients also presented lower leptin than normohydrated patients [20][100]. Considering the possible influence of dialysis in the relationship between leptin–malnutrition–hypervolemia, patients with stage 5 CKD who were not undergoing dialysis were studied, and it was found that those with poor nutritional status also suffered from excessive body fluid and presented lower leptin levels [21][101].
However, dialysis patients with diabetes mellitus and malnutrition–inflammation–atherosclerosis syndrome presented higher leptin levels, and lower HMW adiponectin, than non-diabetic patients with malnutrition–inflammation–atherosclerosis syndrome [22][102], indicating a relationship between the existence of diabetes and enhanced leptin levels.

2.2. Vascular Complications

CKD patients diagnosed with visceral obesity had higher scores for coronary artery calcification and leptin levels, as compared to patients without visceral obesity [23][37]. Vascular calcification is a regulated and complex process involving abnormal cell transitions and osteogenic differentiation, readapting of signaling pathways to those occurring in bones, and, eventually, with the formation of osteoclast-like cells; endothelial cells have been shown to contribute to vascular calcification [24][103]. Studies of CKD patients and in vitro data on human umbilical vein endothelial cells indicate that the higher leptin concentrations promote endothelial dysfunction in CKD [25][26][104,105]. In vitro studies showed that leptin activates the AKT/GSK3β/β-catenin pathway, increasing the levels of ICAM (intercellular adhesion molecule)-1 and VCAM (vascular cell adhesion molecule)-1 and the rearrangement of the cytoskeleton, which results in increased endothelial cell migration and enhanced monolayer permeability, thus, favoring endothelial dysfunction [25][104]. In CKD patients, leptin levels were found to correlate positively with the circulating soluble forms of ICAM-1 and VCAM-1 [25][104]. In patients with stage 3–5 CKD, leptin levels also correlated positively with aortic stiffness [27][106], known to be connected to arterial media calcification [28][107].

2.3. Dyslipidemia

In CKD, leptin and leptin/BMI were found to be independent predictors of total cholesterol and triglyceride values, being associated with a more atherogenic lipid profile [29][108]. In children with CKD stages 2 to 4, leptin levels associated positively with triglyceride values and negatively with HDLc concentrations [8][90]. The HDL/LDL (low-density lipoprotein) ratio was lower in CKD patients as compared to the control group, and correlated with leptin, which suggested that hyperleptinemia observed in CKD contributes to pathogenesis of CVD by decreasing HDL/LDL ratio [3][85]. Furthermore, and as already mentioned, atherogenic dyslipidemia is a component of metabolic syndrome, the occurrence of which is associated with high leptin levels [9][91]. It was also reported that CKD-related alterations of the fatty acid profile may contribute to elevated serum leptin concentrations in patients with CKD by increasing its gene expression in subcutaneous adipose tissue [30][109].

2.4. LVH (Left Ventricular Hypertrophy)

Surprisingly, in ESRD, lower leptin levels have been associated with a poorer prognosis regarding CV events and mortality. Scholze et al. reported that low leptin levels were an independent predictor of mortality in ESRD patients under hemodialysis [31][110]. Even in prevalent kidney transplant recipients, lower leptin was found to be an independent predictor of death [32][111]. In maintenance hemodialysis patients, decreased circulating levels of leptin were associated with a higher risk of CV events and death, probably contributing to LVH and peripheral vascular disease development [33][112]. Qin et al. described that decreased leptin levels were an independent risk factor for LVH development in patients on hemodialysis [33][112]. Curiously, in ESRD, patients with a history of stroke presented higher leptin levels than those without stroke history, while patients with congestive heart failure showed lower leptin values that those without history of congestive heart failure [34][113].

3. Mineral and Bone Disorder

Leptin appears to stimulate osteoblastic proliferation and differentiation and to inhibit adipogenic differentiation from marrow stromal cells; however, as well as positive, also both negative and no effects of leptin in bone mass have been described [35][114]. In ESRD patients, bone mineral density is associated with body composition, in particular total fat mass, nutritional status and mortality risk [36][115]. Leptin levels were found to correlate inversely with markers of bone turnover and parathyroid hormone (PTH), which led to hypothesize that leptin lowers bone turnover in ESRD [37][116]. Wang et al. found that increased leptin, body weight and serum albumin were positively related to bone mineral density in hemodialysis patients [38][117]. Leptin was reported to have a bone-sparing effect in hemodialysis patients, but only when its serum levels were higher than the presumed threshold of blood–brain transport saturation [39][118]. However, PTH, in addition to BMI, insulin and metabolic syndrome score, was found to be an independent predictor of leptin values with both, PTH and leptin, correlating positively in patients at different CKD stages [40][119]. Additionally, it was found that in 29 female hemodialysis patients, leptin levels were lower in those with PTH > 300 pg/mL, bone alkaline phosphatase between 300–600 IU/L and calcium < 8.5 mg/dL, as compared to female with PTH between 100–300 pg/mL, bone alkaline phosphatase < 300 IU/L and calcium between 8.5–10.5 mg/dL, respectively; these results were not found for male patients or when considering all the 73 patients studied, and the values of these biomarkers did not differ significantly between the two genders [41][120].

4. Anemia

An independent association between lower leptin levels and anemia was found, and in stage 5 CKD patients that were submitted to parathyroidectomy, increased leptin was associated with ameliorated anemia and malnutrition [42][121].
In CKD, leptin levels were identified as possible predictors of epoetin sensitivity; in the presence of high leptin levels, proinflammatory cytokines appear not to have inhibitory effects on epoetin sensitivity [43][122]. Hyperleptinemia was reported to better reflect recombinant human erythropoietin response and nutritional status in long-term dialysis patients [44][123]. However, it was reported that dialysis patients with diabetes and malnutrition–inflammation–atherosclerosis syndrome had significantly higher leptin levels and required higher erythropoietin dose; indeed, erythropoietin dosage was associated significantly with levels of leptin and biomarkers of inflammation [22][102].
In ob/ob mice, circulating hepcidin concentrations were found to be significantly lower as compared to control group; after leptin administration, hepcidin levels and liver expression of Hamp mRNA increased [45][124]. Leptin seems to favor the enhancement of hepcidin, the major regulator of iron metabolism, since it inhibits iron intestinal absorption and reduces iron mobilization from macrophages of the reticuloendothelial system.
Data concerning the impact of leptin levels on CKD comorbidities are not always consistent. Conflicting results may be related to renal replacement therapy used, for instance, high-flux hemodialysis and hemodiafiltration were shown to considerably reduce leptin levels [46][47][80,81]. In CKD, the coexistence of complications, such as diabetes mellitus, obesity, metabolic syndrome, and hypervolemia, may also contribute to the contradictory data.

It seems that leptin contributes to a higher risk of CVD events and mortality in CKD patients, but further studies are warranted to fully clarify its role, especially when different comorbidities exist.

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