Pediatric Nephrology

, Volume 28, Issue 4, pp 611–616

Ghrelin and leptin pathophysiology in chronic kidney disease

Authors

  • Sujana S. Gunta
    • Division of Pediatric NephrologyUniversity of California San Diego–Rady Children’s Hospital
    • Division of Pediatric NephrologyUniversity of California San Diego–Rady Children’s Hospital
    • Division of Pediatric NephrologyUniversity of California San Diego
Review

DOI: 10.1007/s00467-012-2380-9

Cite this article as:
Gunta, S.S. & Mak, R.H. Pediatr Nephrol (2013) 28: 611. doi:10.1007/s00467-012-2380-9

Abstract

Ghrelin is an orexigenic hormone with additional effects on the regulation of inflammation and the cardiovascular system. It may play an important role in the pathogenesis of cachexia/protein-energy wasting (PEW), inflammation and cardiovascular complications in chronic kidney disease (CKD). There are three circulating gene products of ghrelin, namely, acyl ghrelin, des-acyl ghrelin and obestatin, each with individual distinct functions. Perturbations of these circulating ghrelin proteins impact the overall milieu of CKD. Leptin is an anorexigenic hormone which is secreted from the adipocytes and interacts with ghrelin and other appetite-regulating hormones. Leptin also plays a role in regulating inflammation and the cardiovascular system. Indeed, ghrelin and leptin may play yin-and-yang roles in CKD pathophysiology. Clinical trials involving the use of the mimetics or antagonists of these hormones are limited to short-term phase I/II studies. Further understanding of their interactions in CKD pathophysiology is needed for potential large-scale clinical trials, which may impact the quality of life and survival of patients with CKD.

Keywords

GhrelinLeptinChronic kidney diseaseCachexiaInflammationCardiovascularMortality

Introduction

Ghrelin is a peptide hormone secreted mainly by the stomach and small intestine. The three circulating gene products of ghrelin are acyl ghrelin, des-acyl ghrelin and obestatin. Acyl ghrelin is an orexigenic hormone while des-acyl ghrelin and obestatin are anorexigenic hormones [1]. Tschop et al. showed that ghrelin induces adiposity in rats and mice by reducing fat utilization and increasing food intake and body weight [2], thereby providing the initial evidence of the role of ghrelin as an appetite-stimulating hormone in addition to its effects in regulating growth hormone secretion. Ghrelin promotes the secretion of neuropeptide Y (NPY) and agouti-related peptide (AgRP), which are both active appetite-stimulating neuro-peptides in the hypothalamus [3]. There is a pre-prandial rise and postprandial fall in plasma ghrelin levels [4]. Ghrelin stimulates gastric acid secretion and gastric motility [5]. It is also involved in carbohydrate metabolism and insulin secretion [6]. Ghrelin has various cardiovascular effects and lowers mean arterial blood pressure, improves left ventricle dysfunction and attenuates the development of left ventricular remodeling and cardiac cachexia [7, 8]. These effects are exerted through vasodilation as well as the inhibition of vascular oxidative stress, pro-inflammatory cytokines and apoptosis of cardiomyocytes [9].

Leptin is an anorexigenic hormone as well as a cytokine produced in adipose tissues. It regulates energy homeostasis through signal transduction in the arcuate nucleus of the hypothalamus where it interacts with NPY and AgRP, acting as an antagonist to ghrelin [10]. The major metabolic action of leptin is mediated through signaling from the hypothalamus to peripheral tissues through the autonomic nervous system [11]. Leptin also influences the hypothalamopituitary–adrenal and hypothalamopituitary–thyroid axes [12, 13]. Fasting decreases plasma leptin concentration, while re-feeding reverses this decline, with leptin playing a role in long-term energy balance. Leptin suppresses food intake by counteracting the activity of neurons containing NPY and AgRP and by increasing the activity of neurons expressing α-melanocyte stimulating hormone (α-MSH) [11]. α-MSH binds to melanocortin receptor (MC-R) and inhibits food intake, primarily via MC4-R; AgRP is an endogenous antagonist of MC4-R [14]. Leptin levels are increased in the obese, but its anorexigenic effects are tampered by leptin resistance [15].

Leptin also promotes angiogenesis by increasing vascular endothelial growth factor levels [16], induces surfactant expression and maturity in the fetal lung [17] and affects reproduction via its effect on energy balance [18]. It affects bone metabolism by reducing cancellous bone and increasing cortical bone [19]. Leptin is also a proinflammatory cytokine; it increases in response to acute infection and plays a role on CD4+ T lymphocyte proliferation, macrophage phagocytosis and the secretion of inflammatory cytokines such as interleukin (IL)-1 and tumor necrosis factor-alpha (TNFα) [20, 21].

Ghrelin and leptin in chronic kidney disease (CKD)

Ghrelin is mainly degraded by the kidney. Total ghrelin levels are elevated in CKD [22]. Ghrelin mRNA levels in the stomach (main production site of ghrelin) of nephrectomized mice are not increased, suggesting that reduced clearance and degradation by the kidney accounts for the elevated circulating levels in CKD [23]. Total plasma ghrelin levels correlate with serum creatinine in adults with various stages of CKD and are increased almost threefold in patients with end-stage renal disease (ESRD) as compared to controls [24, 25]. Compared with controls, in children with CKD or ESRD and a low body mass index (BMI), circulating total ghrelin and obestatin concentrations are elevated, acyl ghrelin levels are not elevated and the acyl/total ghrelin ratio is significantly decreased, all evidence of cachexia/protein-energy wasting (PEW) (Fig. 1) [26]. This profile of increased anorexigenic forms of ghrelin (des-acyl ghrelin and obestatin), probably from reduced clearance in CKD, but with no compensatory increase in acyl ghrelin, which is the active and orexigenic form of the hormone, would indeed favor the development of cachexia/PEW. Furthermore, in these patients, the acyl/total ghrelin ratio positively correlated with albumin level and energy intake and negatively correlated with severity of CKD and growth hormone levels [27].
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Fig. 1

a Plasma levels of acyl and total ghrelin (pg/ml) in patients with chronic kidney disease (CKD), those receiving dialysis treatment [hemodialysis (HD)/peritoneal dialysis (PD)], renal transplant (RTx) recipients and healthy controls. Total ghrelin was increased and acyl ghrelin was reduced in CKD and HD/PD patients compared with healthy controls (P < 0.05). b Plasma levels of obestatin (pg/ml) in CKD, HD/PD and RTx patients and healthy controls. Obestatin levels were significantly increased in CKD and HD/PD patients compared with the RTx patients and healthy controls (P < 0.01). c Body mass index (BMI) standard deviation score (SDS) of patients with CKD, HD/PD and RTx and in healthy controls. BMI was significantly reduced in CKD and HD/PD patients compared with patients after RTx (P < 0.01). The upper and lower limits of the boxes in b and c indicate the 25th and 75th percentiles, respectively, and the whiskers indicate the minimum and maximum values. The middle line separating the boxes represents the 50th percentile. Horizontal lines at top of graphs indicate that the difference between these groups reaches the level of statistical significance shown. Used with permission from Büscher et al. [26]

Leptin is considered to be a counter-regulatory hormone to ghrelin. In a study of energy homeostasis in hemodialysis (HD) patients, acyl ghrelin levels were low and leptin levels were elevated [28]. Leptin is cleared from the circulation by the kidney by glomerular filtration followed by metabolic degradation in the renal tubules, which accounts for the elevated level of leptin in CKD [29]. The Third National Health and Nutrition Examination Survey (NHANES) [30] reported that high plasma leptin level was significantly associated with CKD after adjusting for various factors. There was a stepwise increase in serum leptin levels with decreasing renal function in children with CKD (P < 0.02) [31].

Weight regulation in CKD

Chronic kidney disease leads to the accumulation of the anorexigenic hormones des-acyl ghrelin, obestatin and leptin but does not lead to a compensatory increase in orexigenic hormones such as acyl ghrelin, thus favoring the development of cachexia/PEW.

Experimental studies

Ghrelin administration may have potential benefit in treating cachexia of CKD. Ghrelin induces a significant increase in appetite in both healthy and uremic rodents [2, 32]. In one study, subcutaneous ghrelin administration in CKD rats decreased the muscle wasting secondary to a decrease in muscle protein degradation and improved inflammatory cytokines independent of the changes in food intake [32]. In another study, transgenic mice over-expressing leptin showed a significant decrease in food intake and body weight as compared to controls [33]. Uremia-associated cachexia may be caused by leptin signaling through the MC4-R: Leptin receptor-deficient (db/db), and MC4-R knockout mice resist the cachexic effects of uremia on weight gain, body composition and metabolic rate. Furthermore, the administration of AgRP, a natural neuropeptide antagonistic to MC4-R, to mice with CKD results in increased food intake, normalization of basal metabolic rate and an increase in total body weight and lean body mass [34]. Thus, a leptin antagonist or an antagonist of its downstream signaling pathways, such as MC4-R antagonist, may be useful in the treatment of CKD cachexia/PEW.

Clinical studies

An association between low ghrelin levels and cachexia/PEW has been described in patients on HD [35]. Des-acyl ghrelin levels are significantly higher in anorexic HD patients than in non-anorexic HD patients [36]. On the other hand, an inverse linear correlation between leptin z-score and spontaneous energy intake (P < 0.001) is seen in children with CKD [30]. HD patients with PEW have low ghrelin and high leptin levels, whereas HD patients with no PEW do not have this association [37]. A inverse relationship was found between leptin and triceps skinfold thickness in children with ESRD on HD, in whom leptin levels were significantly higher (P = 0.01) compared to controls (Fig. 2) [38]. A significant increase in serum leptin levels (P < 0.001) was observed in peritoneal dialysis (PD) patients who lost lean body mass, whereas no such change was observed in the patients who gained lean body mass [39].
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Fig. 2

Serum leptin levels in hemodialyzed children and controls according to malnutrition. Used with permission from Besbas et al. [38]

In the setting of patients on maintenance HD, leptin concentrations can be decreased using super-flux polysulfone dialyzers [40]. This may be a therapeutic option to decrease leptin levels and improve cachexia, inflammation and mortality in these patients. There was a spontaneous increase in energy intake in a group of patients on PD with PEW after a single subcutaneous injection of ghrelin [41]. A follow-up study with week-long treatment of daily subcutaneous ghrelin in dialysis patients with PEW resulted in increased circulating ghrelin levels and significant improvement in appetite [42].

Inflammation in CKD

Systemic inflammation in common in CKD, and there is a strong link between inflammation and cachexia/PEW. The mediators of inflammation act on the central nervous system to alter both appetite and metabolic rate [43]. Ghrelin and leptin may be important players in this respect. Ghrelin has anti-inflammatory effects. Ghrelin receptors are expressed on leukocytes and macrophages. Ghrelin causes a decrease in release of inflammatory cytokines [44, 45]. In contrast, leptin is a pro-inflammatory cytokine. Serum leptin concentrations are elevated in patients with CKD and correlate with C-reactive protein (CRP) levels, suggesting that inflammation and hyperleptinemia are associated in CKD [43].

Experimental studies

There is a significant decrease in circulating pro-inflammatory cytokines, such as IL-1α, IL-1β, IL-6 and TNFα in CKD rats treated with ghrelin [32]. Leptin is also a potential mediator of inflammation-induced anorexia. Administration of lipopolysaccharide induces profound anorexia and weight loss in hamsters and increases levels of circulating leptin and adipose tissue leptin mRNA at the same time [46].

Clinical studies

Plasma total ghrelin levels had a positive correlation with TNFα and IL-6 levels and a negative correlation with energy intake in a study of HD patients [47]. It is possible that inflammation may be a cause of the aberrant ghrelin levels in CKD, contributing to the development of cachexia/PEW. Furthermore, HD patients with cachexia have high serum concentrations of CRP and leptin and low serum concentrations of albumin [39]. In a longitudinal study, PD patients who lost lean body mass had higher CRP levels and serum leptin concentrations, whereas no such change was observed in patients who gained lean body mass [39]. These studies suggest that leptin, which is a proinflammatory cytokine, may contribute to the role of inflammation in the pathogenesis of cachexia/PEW in CKD.

Cardiovascular disease in CKD

Cardiovascular disease mortality is very high in patients receiving maintenance dialysis [48], with 28 and 33 % of deaths among children on PD and HD, respectively, attributable to cardiovascular causes, as compared to 3 % in the general pediatric population [49].

Experimental studies

In animal models, ghrelin improves cardiac contractility in heart failure, reduces the infarct size in a rat ischemia–reperfusion model and attenuates the reduction in left ventricular function induced by ischemia–reperfusion [5, 6]. Intracerebroventricular infusion of leptin in rats causes increased arterial pressure [50]. Subcutaneous administration of leptin causes systolic hypertension, induces systemic and intrarenal oxidative stress and stimulates renal sodium tubular reabsorption [51].

Clinical studies

In a prospective study of long-term HD patients, low serum acyl ghrelin was associated with the development of cardiovascular disease in a multivariate analysis model, but there was no association with total ghrelin levels [52]. Daily administration of ghrelin in malnourished HD patients produced a significant reduction in systolic and diastolic blood pressure for up to 2 hours after ghrelin injection, with average reductions of 10.4 mmHg systolic and 4.7 mmHg diastolic pressures [42]. Low total ghrelin and high leptin levels in cachectic HD patients have been associated with high cardiovascular mortality [31].

A positive correlation was noted in protein C and serum leptin levels in PD patients. In a subset of ESRD patients receiving treatment with erythropoietin, this positive correlation was also seen with tissue factor inhibitor pathway, platelet aggregation and thrombomodulin. This result suggests that leptin may also contribute to thrombotic complications seen in PD patients [53]. Clinical studies have shown a significant positive correlation between leptin and blood pressure independent of body adiposity in both normotensive and hypertensive individuals [54].

Survival in CKD

End-stage renal disease patients on HD with inflammation-associated PEW and low ghrelin concentrations have been shown to have high cardiovascular as well as all-cause mortality. Survival analysis showed a detrimental impact of low ghrelin values. The multivariate hazard ratio was significantly higher for cardiovascular mortality and all-cause mortality in CKD patients with PEW and low ghrelin levels as compared to CKD patients with no PEW and high ghrelin levels [31]. CKD patients with PEW and high mortality also had abnormally high leptin concentrations, even after correction for BMI.

Biomarkers for mortality in ESRD include traditional cardiovascular risk factors, inflammation and PEW. Ghrelin is involved in the pathogenesis of all three of these pathways and may therefore be a very powerful biomarker for survival outcomes in patients with ESRD [55]. Leptin is probably also involved in all three pathways, although the evidence for leptin is less convincing (Fig. 3).
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Fig. 3

Overlap of involved pathways in the pathophysiology of ghrelin and leptin in chronic kidney disease

Summary

Leptin and ghrelin may play important yin-and-yang roles in CKD pathophysiology, a complex interaction affecting energy homeostasis, systemic inflammation and the cardiovascular system, which in turn may ultimately affect survival outcomes in CKD. Further understanding of the mechanism and interaction of these hormones will pave the pathway for long-term clinical trials using mimetics and antagonists of these hormones. This may be a promising approach for improving the morbidity and mortality in patients with CKD.

Acknowledgments

Robert Mak is supported by the National Institute of Health U01 DK066143 grant and investigator-initiated grants from the Cystinosis Foundation and Abbott Inc.

Conflicts of interest

None.

Copyright information

© IPNA 2012