Which is the Role of Leptin on Patients in the End Stage
of Renal Disease?
Vaia
D. Raikou
Vaia D. Raikou, 1st Dpartment of Medicine,
Propaedaetic, National & Kapodistrian University of Athens, School of
Medicine, Athens, Greece
Correspondence to: Vaia D. Raikou,
PhD, 1st Dpartment of Medicine,
Propaedaetic, National & Kapodistrian University of Athens, School of Medicine,
Athens, Greece
Email: vraikou@med.uoa.gr
Telephone: +302107456261
Fax: +302107791839
Received: May 15, 2015
Revised: June 9, 2015
Accepted: June 12, 2015
Published online: June 26, 2015
ABSTRACT
Leptin is a small peptide
hormone (16 kDa), a product of the obesity gene (Ob), and is mainly synthesized
and secreted by adipocytes.In this review paper the main points of the leptin
role on the end stage of renal disease is out lined.
© 2015 ACT. All
rights reserved.
Key words: Leptin; Dialysis; Inflammation; Arterial stiffness;
Cardiovascular disease
Raikou VD. Which is the
Role of Leptin on Patients in the End Stage of Renal Disease? Journal of
Nephrology Research 2015; 1(1): 10-14 Available from: URL:
http://www.ghrnet.org/index.php/jnr/article/view/1137
INTRODUCTION
The end-stage of renal disease (ESRD) is characterized by increments of
plasma concentrations of hormones produced by adipose tissue known as adipocytokines
(including leptin, resistin, tumor necrosis factor-alpha and adiponectin),
possibly caused by both passive accumulation from reduced renal excretion and
metabolic abnormalities induced by uremia[1]. Leptin, which belongs
to IL6 family of cytokines, related to diminished food intake. Since leptin is
mainly secreted by adipose tissue, serum leptin levels are directly
proportional to adipocyte mass. Apart from metabolism, leptin has systemic
effects including regulation of angiogenesis, wound healing, lipolysis, blood
pressure homeostasis, reproduction, hematopoiesis and immune function[2,3].
The current studies provide evidence that the real role of leptin on the
patients in end stage of renal disease is complicated rather than clear.
Leptin,
inflammation, malnutrition and insulin resistance
It has been already
recognized that a substantial number of patients with end-stage renal disease
have serologic evidence of an activated inflammatory state[4].
Previously, the leptin receptor has been identified on endothelial cells, and
leptin has been reported to promote both angiogenesis and inflammation[5].
Leptin modifies the systemic inflammatory response and the inflammatory
microenvironement in renal disease may be associated with elevated expression
of leptin gene[6]. However, there is a discrepancy for the
relationship of leptin levels with chronic inflammation and it has been
supported that leptin may be a negative acute phase protein in chronic
hemodialysis patients[7]. On the other hand, leptin suppresses
appetite and increases energy expenditure, playing a homeostatic role in the
regulation of food intake and in maintaining body composition in general
population[8]. In patients with end-stage renal disease malnutrition
and hypoalbuminemia are common and powerful predictors of morbidity and
mortality in this population[9]. One potential relationship between
malnutrition and inflammation in renal disease patients is appetite suppression
and the link between inflammation and anorexia may be through the leptin[10].
However, it has been already supported that inflammation is unlikely to reduce
appetite causing malnutrition in dialysis patients through a leptin-mediated mechanism,
because leptin is a negative rather than a positive acute phase protein in this
population of patients[7]. Also, recent study reported that leptin
levels were elevated in ESRD patients with normal and mild malnutrition,
although were lower in severe and moderate category of malnutrition score[11]
in agreement with other previous findings[12]. The decreased serum
levels of leptin in severe category of malnutrition group might be associated
with acquired leptin receptor resistance[11].
However, it
has been showed that the levels of acyl ghrelin were lowest in the severe group
of malnutrition[11]. Ghrelin is an appetite stimulating hormone and
transduces signals to hypothalamic regulatory nuclei that control energy
homeostasis. Ghrelin is shown to enhance food intake in dialysis patients with
mild to moderate malnutrition[13]. It has been reported that low
acyl ghrelin is associated with poor nutritional status and loss of appetite[14]
.Leptin, ghrelin and uncoupling protein2 (UCP2) gene polymorphisms are the
molecules which implicated in the appetite-energy regulatory pathway of the
malnutrition-inflammation syndrome in ESRD[11]. UCP2 is an inner
mitochondrial protein implicated in thermogenesis and reduction of reactive
oxygen species, thus it leades to generation of heat and resting energy
expenditure. Elevated functions of UCP2 are associated with increased total fat
mass in dialysis patients, which is a protective condition as higher amount of
fat signifies more energy stores in these patients[15].
On the other
hand, leptin decreases hypothalamic NPY levels and enhances sympathetic
activity with hyperinsulinemia, resulting in appetite suppression and
modulation of insulin sensitivity[1]. High leptin triggers insulin
resistance and vice versa[16].
Our studies in
dialysis patients showed that the patients with higher leptin serum
concentrations had more activated inflammation and insulin resistance, in
comparison to the patients with lower leptin values, leptin acting as a
positive rather than as a negative acute phase protein[17,18] ,
inversely to the previous reports[7]. Also, in our studies the
relationship between leptin serum concentrations and inflammation defined by
the serum concentrations of high sensitivity C-reactive protein (hsCRP), and
insulin resistance defined by homeostasis model assessment insulin resistance
(HOMA-IR) was found significantly positive (Figures 1 and 2).
Leptin,
metabolic acidosis and arterial stiffness
It has been shown using experimental methods, that leptin induces
reactive oxygen species (ROS) generation by increasing fatty acid oxidation via
a protein kinase A (PKA) activation, which may play an important role in the
progression of atherosclerosis in insulinresistant obese diabetic patients[19]
and leptin may contribute to oxidative stress and acidosis status of obese
patients[20].
Metabolic
acidosis is a common condition in end stage renal disease patients resulting in
inflammatory stimulation, lipids oxidation and oxidative stress[21].
Maintenance dialysis therapies are often not able to completely correct the
base deficit. It has already been reported the role of metabolic acidosis on
vascular calcification, as the mineral metabolism disturbances act through the
existing metabolic acidosis in dialysis patients[22]. Even though
the influence of acidosis on vascular calcification is complicated, acidosis
promotes inflammation of the arterial wall, releasing cytokines that may induce
vascular calcification and arterial stiffness[22]. Arterial stiffness,
assessed as carotid-femoral pulse wave velocity (c-f PWV) and carotid
augmentation index (Aix), was associated with abnormalities in the structure or
function of the vascular wall and has shown to be an important parameter for
the assessment of cardiovascular risk among the markers of arterial disease[23].
Recent study
showed that the hyperleptinemia was associated inversely with vasodilatation of
resistance arteries in elderly population of 1,016 subjects[24].
Additionally, another previous studies had observed a positive association
between c-fPWV, as an indicator of arterial stiffness, and leptin/adiponectin
ratio adjusted for gender and age and suggested that leptin regulates the
osteoblastic differentiation and calcification of vascular cells and that the
artery wall may be an important peripheral tissue target of leptin action[25].
Recently, it has been reported that leptin causes endothelial dysfunction and
enhances the activity of angiotensin II on blood pressure, activating the
sympathetic nervous system and contributing to vascular stiffness and
hypertension in obesity[26].
Controversialy
to the above reported previous studies, our previous study showed that dialysis
patients with higher leptin serum concentrations had a better acidosis state
assessed by mildly higher serum bicarbonate levels in combination to lower
arterial stiffness, than the patients with lower leptin (Figure 3)[27].
However, the previous studies used mainly elderly or obese subjects and not
patients on the end stage of renal disease. The group of patients on the
end-stage of renal disease, is different than elderly or obese population and
in these patients very complicated pathophysiological mechanisms may be
activated resulting in a vital balance between multiple inverse reactions. The
increased leptin serum concentrations may have an inverse relationship with
arterial stiffness, due may to better acidosis status, which in turn may be
connected to elevated leptin values in dialysis patients.A such finding may be
a reverse causality or a compensatory and protective mechanism versus to the
hurtful actions of the increased leptin serum concentrations in these patients.
Alternatively, the negative relationship between leptin and arterial stiffness
could also show that leptin may be the mediator for the relationship between
metabolic acidosis and impaired vascular function in this population of
patients.
Leptin in
atherosclerosis and cardiovascular disease
Disorders associated with hyperleptinemia such as obesity and insulin resistance
are major risk factors for cardiovascular disease[28]. Enhanced
chronic systemic inflammation and reduced insulin sensitivity are often
associated in patients with chronic renal disease, contributing to
cardiovascular morbidity and mortality in these patients[29].
Strong
evidence indicates that there is an important role for leptin on hypertension[30].
The role of leptin on cardiovascular system to maintain normal blood pressure
seem to be balanced in lean individuals with normoglycaemia and leptin
sensitivity.Its actions refer to blood pressure lowering mechanisms (via
vasodilation, by promoting nitric oxide release from the endothelium), but also
to mechanisms that increase blood pressure[31]. Controversialy, in
obese hyperleptinemic or other leptinresistant conditions as in renal disease,
the homeostatic control of blood pressure is impaired. Also, it has been
reported the relationship of leprin with atherogenesis, angiogenesis,
thrombosis, migration and proliferation of smooth muscle cells[32,33].
Previous study using experimental model showed that leptin-deficient mice
developed significantly less atherosclerosis and exogenous leptin significantly
increased atherosclerosis[34].
Given the above
actions, serum leptin levels are reported to be associated with various
cardiovascular risks, including stroke, chronic heart failure, acute myocardial
infarction[35], coronary heart disease, and left cardiac
hypertrophy. Evidence suggests that leptin can stimulate inflammatory response
by activating TNF-α via p38 and JNK MAPK pathway[36] and these
inflammatory markers may be associated with the risk of recurrent myocardial
infarction and death. The normal physiological effect of leptin on the
regulation of TNF-α expression seems to be suppressive, but the hyperleptinemic
condition and leptin resistance may both contribute to the rise of TNF-α in the
adipose tissue in obesity[36]. Also, several pieces of evidence
indicate that TNF-α plays an important role on insulin resistance observed
during obesity, which in turn contributes to several pathological problems of
obese patients such as hyperlipidemia, arteriosclerosis and hypertension.
Because of leptin and TNF-α are overproduced in the adipose tissue of obese
individuals and released into the circulation, both may activate inflammatory
response and could be involved in the pathogenesis of the CVD during obesity[37].
Additionally,
leptin induced expression of monocyte chemoattractant protein-1 (MCP-1), a CC
chemokine, which plays an important role in the early phase of atherosclerosis
by initiating monocyte/macrophage recruitment to the vessel wall[38],
and its expression is actually known to be up-regulated in human
atherosclerotic plaques[39].
On the other
hand, it has been reported an inverse link between leptin, bone mass and PTH in
dialysis patients suggesting that leptin may be implicated in low bone turnover
in these patients, likely by the function of central nervous system.Also, leptin
may be unrelated to valvular calcification in uremic patients, but it predicts
incident cardiovascular events in overweight and obese dialysis patients and it
seems to be a connector between bone and cardiovascular alterations in patients
with end stage of renal disease[40].
By contrast,
some data indicated that leptin may protect against atherosclerosis in specific
animal models and human subjects[38]. There are reports which
revealed that low serum levels of leptin are independent predictors of mortality[12,41].
Recent study reported that low serum leptin concentration is an independent
risk factor of all-cause mortality in stable maintenance hemodialysis patients,
but may not be linked with CVD-related mortality[42].
Moreover,
another previous study did not support the presence of a clinically relevant
relationship between adipocytokines (leptin, adiponectin or resistin) and
previous episodes of vascular disease in end stage of renal disease patients,
with the only exception of a relationship between resistin levels and heart
disease[43].
Conclusions
The current data in renal disease patients and also in general
population suggests that the net effects of leptin on the pathways of
cardiovascular diseases are complicated rather than clear and not completely
understood.Leptin may have both, protective and harmful effects on the
cardiovascular system. However, the most important risk factor should be the
leptin resistance rather than the leptin levels themselves, acting via the
stimulation of TNF-α and insulin resistance, which are the main
pathophysiological pathways for cardiovascular disease, in combination to some
role of bone mass.Despite the elevated leptin levels activate inflammatory
process, they are inversely associated with metabolic acidosis status, arterial
stiffness and vascular function showing a protective action of leptin in this
population of patients.Also, leptin levels are increased mainly in mild than in
high malnutrition score and ghrelin may be major marker contributing to malnutrition
among ESRD patients, rather than leptin.Further studies on appetite and energy
homeostasis regulating markers are required for establishing their role in
malnutrition.
CONFLICT OF INTERESTS
The author declare no conflict of interest.
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Peer
reviewer:
Ming-Jiang Xu, MD, PhD, Associate
Professor, Laboratory of Liver Diseases, National Institute on Alcohol Abuse
and Alcoholism, National Institutes of Health, 5625 Fishers LN, 2S12,
Rockville, MD 20852, USA.
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