Leptin in renal failure

Leptin

in Renal Failure

Christos S. Mantxoros, MD, DSc*

Leptin, an adipocyte-derived hormone, signals to the brain information on the amount of energy stored in adipose tissue and regulates energy homeostasis. In addition, leptin has been implicated in the regulation of neuroendocrine function, growth, hematopoiesis, and immune regulation. Plasma leptin is cleared by the kidney, and thus, leptin levels are elevated in hemodialysis patients. Whether the elevated leptin levels in hemodialysis patients contribute to the pathophysiology of the clinical manifestations of renal failure in humans remains to be conclusively shown in the future. o 7999 by the National Kidney Foundation, Inc.

R

ESEARCH ON energy homeostasis has been intensified after the discovery of leptin in 1994.i However, accumulating evidence suggests that the role of leptin is much broader than that of an energy homeostasis regulator. This adipocyte-derived hormone affects several neuroendocrine mechanisms and regulates many systems, including the hematopoietic and immune systems. Because leptin levels are increased in renal failure, a role for leptin in the pathogenesis of renal failure-associated malnutrition has been suggested and is currently the focus of ongoing research studies.

Leptin

Genetics

and Physiology

The ob gene, now called leptin from the Greek word leptos, ie, thin, is mainly expressed in white adipose tissue, ‘8’ but has also been found in the stomach, the placenta, and the mammary gland.3 Leptin mRNA encodes a 167 amino acid protein, with a 21 amino acid-signaling peptide. Leptin, which circulates in plasma in the free form and plasma bound to leptin-binding proteins, is a member of the cytokine family.4,5

*Assistant

Pro~~sor,

Divixion

of Endocrirzology,

Departwzmt

of

Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA. Supported by the Clirtical Associate Physician Award (NIH and Beth Israel Deaconerr Medical Center), the Hershey Family and theJmior Investigator Award (Beth Israel Deaconess Medical Cerzter and Hawavd Medical Award

School), (P30 DK

and the Boston 46200).

Obesity

Nutn’fion

Research

Center

Address reprint requesti to Christos S. Mantzoros, MD, DSc, Division of Endocrinology, RN 325, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215. 0 1999 by the National IOSI-2276/99/0903-0004$3.00/O

122

Kidney

Fol&ntion,

Im.

Leptin levels are positively and strongly associated with the amount of energy stored as fat and are also influenced by prolonged fasting or overfeeding.2,6 The composition of the diet and hormonal factors also regulates leptin levels.7s More specifically, insulin and possibly glucocorticoids may increase circulating leptin levels, whereas adrenergic receptor agonists reduce leptin levels.9-*3 Several cytokines, such as tumor necrosis factor a (TNFa) and interleukins 1 and 6, also alter leptin mRNA expression and circulating levels.14-17 Finally, women seem to have higher leptin levels than men, and several transcription factors regulate the leptin gene promoter.2,18 Plasma leptin levels display a significant ultradian and circadian variation with a distinct nocturnal whether, in peak 19,2o but it remains unknown addition to influencing leptin levels, any of the above factors also influence leptin pulsatility.

Leptin

Action

and Clearance

Leptin acts by activating specific leptin receptor isoforms. 21 Leptin reaches the brain via a saturable and it acts to decrease transport mechanism, energy intake and increase energy expenditure. In the brain, the long leptin receptor isoform activates the JAK-STAT system @AK-signal transducer and activator of transcription) and alters expression of many orexigenic or anorexiogenic hypothalamic neuropeptides.2” These neuropeptides include, but are not limited to, neuropeptide Y (NPY), melanocyte-stimulating hormone (aMSH), agouti-related protein (AGRP), proopiomelanocortin (POMC), and cocaine and amphetamine regulated peptide (CART).23,24 The relation of other hypothalamic neuropeptides, Jownal

ofRenal

Nutrition,

Vol9,

No 3 (July),

1999: pp 122-125

LEPTIN

IN RENAL

such as ore&, melanin concentrating hormone (MCH), neurotensin, and cholecystokinin (CCK) with leptin, is now being studied.25,26 Recent evidence suggests that the leptin pathway for regulation of energy homeostasis is independent of the serotonin and the MC4 receptor pathways,23,24 suggesting that the system regulating energy homeostasis in humans has built-in redundancy. Treatment with leptin results in dramatic weight loss in animals, but results of phase III studies in humans have not yet been reported. However, it is currently known that only a distinct minority of human obesity is caused by leptin deficiency. In contrast, most cases of human obesity are caused by leptin resistance either at the level of the blood brain barrier or intracellulary (postreceptor defects). Leptin receptors are also expressed in peripheral tissues, including the lung, kidney, liver, pancreas, adrenals, ovaries, hematopoietic stem cells, and skeletal muscle.27-30 It seems that short receptor isoforms in the kidney mediate leptin clearance,27*28 whereas those in the brain capillary endothelium and choroid plexus transport leptin via a saturable system.29,30

Leptin’s

Role in Renal Physiology and Pathophysiology

Because malnutrition is a common problem in patients with advanced chronic renal failure, it has been hypothesized that increased leptin levels may be contributing directly to this frequent cause of morbidity and mortality in renal patients. Several studies have shown that leptin levels are increased in patients with end-stage renal disease independent of fat mass,31-34 a finding consistent with the role of the kidneys to clear leptin from the circulation. Moreover, it has been shown that increased leptin levels in renal failure are a result of an increase in the free bioactive form of leptin. 32 In addition to suboptimal clearance of leptin by the kidneys, immune or metabolic factors could also be responsible for the elevated leptin levels in renal failure. Serum levels of insulin and cytokines are increased in renal failure, and both could contribute to increasing leptin levels. These observations raise the intriguing possibility that leptin may mediate the effect of inflammatory conditions on anorexia.35 In addi-

123

FAILURE

tion, it has also been hypothesized that increased leptin levels may also be related to the elevated energy expenditure of hemodialysis patients and could further contribute to the negative energy balance of these subjects.36 Thus, although in the short term leptin may function as a potassiumsparing diuretic/natriuretic factor, in the long term leptin increases norepinephrine turnover and sympathetic nerve activity.37-40 This results in increased energy expenditure and blood pressure levels in rodents,39,41 but a potential role of leptin in the pathogenesis of hypertension in humans remains to be conclusively shown in the future. Leptin may also play a role in the pathogenesis of insulin resistance, a condition closely related to 41,43 Insulin resistance has renal failure in humans. been associated with increased leptin levels in one study in humans,44 and it improves in response to leptin administration in mice, but similar data in humans have not yet been published. In view of the above actions of leptin, it has been proposed that the hyperleptinemia of uremic patients could explain their sodium-sensitive hypertension and insulin resistance.35 Another potentially important action of leptin that could be of clinical significance in patients with renal failure is the recently reported proliferative effect of leptin on hematopoietic stem cells and the possible synergy between leptin and erythropoietin in regulating hematopoiesis. 45 This may indicate that in conditions such as renal failure, which are characterized by anemia and insufficient production of erythropoietin, hormones like leptin may have an increasingly important role in regulating erythropoiesis. 35 All these findings, albeit intriguing, have been derived from observational studies and thus need to be confirmed by intervention studies in uremic patients.

Synopsis The discovery and study of leptin has significantly increased our understanding of the system responsible for energy homeostasis. Moreover, the pleiotropy of leptin’s actions in human physiology, in association with the increased leptin levels in renal failure, suggests a functional role of leptin in several clinical manifestations associated with renal failure, such as cachexia, insulin secretion and sensitivity, sodium excretion, hematopoi-

124

CHRISTOS

S. AlANTZOROS

esis, and immune function. Thus, more studies are needed to explore the potential role of increased leptin levels in end stage renal disease and to determine whether uremic patients are resistant, or sensitive, to certain actions of leptin. The availability of leptin analogues and leptin receptor antagonists for clinical investigations in the near future is expected to further enhance our understanding of these phenomena and hopefully lead to therapeutic advances.

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