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Part 9: Miscellaneous Complications and Pathophysiologic Mechanisms |
Division of Pediatric Nephrology,1 Oregon Health and Science University, Portland, Oregon, and Division of Pediatric Nephrology,2 University of California at San Diego, La Jolla, California, U.S.A.
Correspondence to: R.H. Mak, Division of Pediatric Nephrology, University of California at San Diego, 9500 Gilman Drive, MC 0831, La Jolla, California 92093-0831 U.S.A. romak{at}ucsd.edu
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ABSTRACT |
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 TOP ABSTRACT ROLES OF ADIPOKINES IN...ROLE OF GUT HORMONES...CONCLUSIONSREFERENCES |
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Cachexia is common in end-stage renal disease (ESRD) patients, and it is
an important risk factor for poor quality of life and increased mortality and
morbidity. Chronic inflammation is an important cause of cachexia in ESRD
patients. In the present review, we examine recent evidence suggesting that
adipokines or adipocytokines such as leptin, adiponectin, resistin, tumor
necrosis factor
, interleukin-6, and interleukin-1β may play
important roles in uremic cachexia. We also review the physiology and the
potential roles of gut hormones, including ghrelin, peptide YY, and
cholecystokinin in ESRD. Understanding the molecular pathophysiology of these
novel hormones in ESRD may lead to novel therapeutic strategies.
KEY WORDS: Inflammation; cachexia; end-stage renal disease; ESRD; adipokines; ghrelin; peptide YY; cholecystokinin.
Cachexia is prevalent in patients with end-stage renal disease (ESRD), and
it has been associated with high morbidity and mortality rates. Elevated serum
concentrations of proinflammatory cytokines such as tumor necrosis factor
(TNF-), interleukin-6 (IL-6), and interleukin-1β
(IL-1β) have been implicated in the pathogenesis of cachexia
(1–5).
These cytokines are also adipocytokines because they are synthesized in
adipose tissues.
Serum TNF-, IL-6, and IL-1β are significantly increased in
patients with renal failure. In hemodialysis (HD) patients, exposure to
dialysis tubing and dialysis membranes, poor quality of dialysis water,
back-filtration or back-diffusion of contaminants, and foreign bodies in
dialysis accesses may be additional causes of inflammation. Similarly, in
peritoneal dialysis (PD) patients, episodes of overt or latent peritonitis,
the PD catheter and its related infections, and constant exposure to PD
solution may contribute to inflammation in these patients. Levels of
TNF-, IL-6, and IL-1β are increased in HD and PD patients alike,
and have been negatively correlated with nutrition status. Higher levels of
TNF-, IL-6, and IL-1β are associated with shorter patient
survival. Plasma levels of TNF- are higher in PD patients with anorexia
and vomiting than in patients without those symptoms
(6).
Expressed both in adipose tissue and in the hypothalamus, IL-6 is involved
in controlling body composition. In pre-dialytic children with chronic kidney
disease (CKD), serum levels of IL-6 were increased and inversely correlated
with creatinine clearance, a marker of renal function decline. Interleukin-6
also directly stimulates muscle protein breakdown and may contribute to the
pathogenesis of uremic cachexia. Suramin, an antiprotozoal drug, known to
inhibit the interaction of TNF- and IL-6, reduced the severity of
cancer cachexia (7). Further
studies are needed to define the roles of these cytokines in uremic
cachexia.
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ROLES OF ADIPOKINES IN ESRD |
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TOPABSTRACTROLES OF ADIPOKINES IN...ROLE OF GUT HORMONES...CONCLUSIONSREFERENCES |
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,
IL-1β, IL-6, IL-8, and IL-10. Adipokines have been shown to have a variety of local, peripheral, and central effects. These secreted proteins are involved in a variety of complex processes, including fat metabolism, feeding behavior, homeostasis, vascular tone, energy balance, and insulin sensitivity. Adipose tissue is a significant contributor of increased systemic inflammation in ESRD patients (8,9).
Leptin: Leptin, a proinflammatory adipokine, is produced mainly by white adipose tissue, and it is cleared by the kidney. Leptin is a member of the IL-6 superfamily of cytokines. Leptin regulates energy homeostasis by inhibiting food intake and upregulating energy consumption. Levels of leptin are significantly increased in dialysis patients, even after correction for body mass index. In dialysis patients, increased leptin levels are associated with markers of poor nutrition status such as low serum albumin and high protein catabolic rate. In CKD, leptin levels increase with declining renal function, presumably as a function of reduced renal clearance.
Leptin concentration relative to percentage body fat is inappropriately elevated in children with CKD and is inversely correlated with dietary nutrient intake. Longitudinal studies showed that PD patients with cachexia and loss of lean body mass during the observation period had higher initial levels of C-reactive protein. A significant increase in serum leptin concentration was observed in PD patients who had lost lean body mass, but no such change was observed in PD patients who gained lean body mass. That finding suggests that hyperleptinemia may be an important cause of uremic cachexia (1,4,5,9).
We tested the hypothesis that leptin is an important cause of uremic cachexia by its receptor signaling. All animals used in the study had the same genetic background (C57BL/6J). Our results showed that uremic cachexia was attenuated in B6.Cg-m+/+Leprdb/J mice, a model of leptin receptor deficiency. Nephrectomy in these animals did not result in any change in weight gain, body composition, resting metabolic rate, and efficiency of food consumption. Furthermore, experimental uremic cachexia could be ameliorated by blocking leptin signaling through the hypothalamic MC-4R. The MC-4R knockout mice or C57BL/6J mice that were administered agouti-related peptide, a MC-4R and MC-3R antagonist, resisted uremia-induced loss of lean body mass and maintained normal basal metabolic rates. Thus, inhibition of leptin signaling may provide a novel therapeutic strategy for inflammation-associated cachexia in CKD (1–5).
Adiponectin: Adiponectin is an adipocyte hormone involved in glucose and lipid metabolism. Interest concerning adiponectin derives from its potential protective role for the cardiovascular system. Plasma adiponectin levels were decreased and were inversely related to the severity of cardiovascular injury in patients with coronary artery disease and with type II diabetes (10). Patients with ESRD and low plasma adiponectin levels had a high risk of cardiovascular death (9,10). The multiple links between adiponectin and several metabolic risk factors such as glucose, triglycerides, insulin, and high-density lipoprotein cholesterol in CKD patients are all compatible with the hypothesis that adiponectin is a protective factor.
The anti-inflammatory activities of adiponectin extend to inhibition of
IL-6 production accompanied by the induction of the anti-inflammatory
cytokines IL-10 and IL-1 receptor antagonist. Inhibition of nuclear factor
B by adiponectin might explain at least some of those effects
(11,12).
Thus, replenishment of adiponectin might represent a novel therapeutic
treatment for ESRD, because increased adiponectin levels might have
anti-inflammatory benefits that inhibit atherogenesis and reduce the risk of
cardiovascular disease in patients.
Resistin: Resistin, a recently discovered peptide hormone, is synthesized and secreted from adipose tissue. Abnormal expression of resistin has been associated with insulin resistance, glucose intolerance, adipocyte differentiation, and inflammation (12). Resistin levels are elevated in both diet-induced obesity and genetic models of combined obesity and diabetes (13). Recombinant resistin reduces insulin sensitivity in mice, and antibodies against resistin block that effect. Deletion of the resistin gene was associated with increased activity of adenosine monophosphatase–activated protein kinase in hepatocytes, decreases in gluconeogenic enzymes and decreases in hepatic glucose production. When fed with either a normal or a high-fat diet, resistin-deficient mice showed significantly better glucose tolerance than did wild-type mice (14).
Resistin also exerts direct vasoactive effects in cultured endothelial cells; augments the expression of cell adhesion molecules such as vascular cell adhesion molecule 1 and monocyte chemoattractant protein 1, key processes in early atherosclerotic lesion formation; influences proinflammatory effects on smooth muscle cells; and affects lipid metabolism in mice (15). The kidney is an important site of resistin clearance, because elevated resistin levels have been associated with decreased glomerular filtration rate and inflammation in CKD patients (16).
Human resistin is only 64% homologous with its murine counterpart, and both are members of the family of resistin-like molecules, which are C-terminal cysteinerich proteins. Given the diverse roles and tissue specificities of this protein family and the low homology between the rodent and human forms, it is unclear at present whether human resistin plays a role similar to that of murine resistin—and if it does, how important human resistin is in ESRD.
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ROLE OF GUT HORMONES IN ESRD |
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TOPABSTRACTROLES OF ADIPOKINES IN...ROLE OF GUT HORMONES...CONCLUSIONSREFERENCES |
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Ghrelin: Ghrelin is secreted primarily from the stomach, small intestine, and colon. In addition to its predicted effect on growth hormone secretion, ghrelin has an important role in the short-term regulation of appetite and the long-term regulation of energy balance and glucose homeostasis. Circulating ghrelin is cleared by kidney and liver (17).
Administration of ghrelin increases feeding in multiple species, including in humans (18,19). Central administration of ghrelin increases food intake primarily by reducing the time between meals, lending credence to the notion that endogenous ghrelin is a "hunger hormone" that signals for food intake. Whether endogenously produced ghrelin directly stimulates food intake through the central melanocortin system or also at the periphery by altering vagal afferent firing is still a matter of debate. Plasma ghrelin levels exhibit a pronounced diurnal variation, are increased by fasting and before meals and at night, and are rapidly (within less than 1 hour) suppressed by food intake, particularly by high-calorie or high-carbohydrate meals (20).
Elevated plasma ghrelin concentrations have been shown in advanced renal failure and HD patients. A recent study described a significant increase in plasma ghrelin in CKD patients as compared with patients having normal renal function, and a correlation between plasma ghrelin and both serum creatinine and growth hormone levels (21). However, the radioimmunoassay used in most studies measures both active acyl and inactive desacyl or fragmented ghrelin protein. In rodents, a preponderance of circulating immunoreactive ghrelin has been reported to be inactive (desacyl) with an estimated ratio of inactive to active (acyl) ghrelin protein of approximately 10:1. The acylated form is thought to be essential for ghrelin activity on appetite and nutrition. Administration of subcutaneous ghrelin, as compared with placebo, significantly increased mean absolute energy intake in PD patients. When expressed as a proportional energy increase for each individual, ghrelin administration resulted in an immediate doubling of energy intake, suggesting that subcutaneous ghrelin administration might improve short-term food intake in dialysis patients with mild-to-moderate malnutrition (22). However, the modest short-term weight gain produced by ghrelin administration was primarily attributable to body fat gain with very little beneficial effect on lean body tissues. Body weight gain in ghrelin-treated rats is caused by an augmentation in fat mass without changes in longitudinal skeletal growth and lean mass (23,24). Such studies are supported by other in vitro experiments in which ghrelin stimulated the differentiation of pre-adipocytes and antagonized lipolysis, suggesting that ghrelin acts directly on adipocytes to stimulate adipogenesis (25). Ghrelin has direct effects on brown adipose tissue, decreasing adiponectin expression (26).
PYY: The 36-amino-acid hormone PYY has been localized in the terminal ileum, colon, and pancreatic islets in humans. It is also located in the central nervous system in low concentrations. Levels of PYY are low in the fasting state and are released in response to food intake, acting to inhibit gastric motility and gastric acid and insulin secretion. Although influenced by both the calories in and the composition of food consumed, PYY levels reach their highest levels 1 – 2 hours post ingestion.
In humans, infusion of PYY3-36 resulted in reduced cumulative 24-hour food intake (27). Plasma levels of gut-derived hormones such as PYY, gastrin-releasing peptide, motilin, neurotensin, pancreatic polypeptide, somatostatin, substance P, and vasoactive intestinal peptide were increased in HD patients as compared with 10 healthy subjects, suggesting that elevated levels of gastrointestinal peptides in CKD patients may contribute to uremic gastrointestinal symptoms and dysfunction (28). However, the current assay for PYY is insufficiently accurate and reproducible to draw definite conclusions.
CCK: The peptide CCK, which is distributed widely throughout the gastrointestinal tract and the central nervous system, has a number of physiologic effects, including stimulation of gallbladder contraction and pancreatic and gastric acid secretion, slowing of gastric emptying, and suppression of energy intake (29). Release of CCK occurs in response to food intake, stimulated largely by the absorption of fatty and amino acids through the walls of the gut. The CCK peptide induces satiety through CCK-A receptors on vagal afferents (30).
High plasma levels of CCK have been negatively associated with nutrition status in dialysis patients (31,32). Exogenous administration of CCK reduced short-term food intake in rodents and humans. Chronic administration of CCK reduced meal size, but effected no overall change in daily caloric intake or body weight, because of a compensatory increase in meal number. Together with leptin, CCK works synergistically to regulate food intake (33).
Gastrointestinal motility disorders are common in ESRD. Gastroesophageal reflux has been found in about 70% of infants and children with ESRD suffering from vomiting and feeding problems (33). Gastric dysrhythmias and delayed gastric emptying have also been found. Serum levels of several polypeptide hormones involved in the modulation of gastrointestinal motility—CCK, gastrin, and neurotensin, for example—are significantly elevated as a consequence of ESRD and can be returned to normal by renal transplantation (34). By directly affecting the smooth muscle of the gut or stimulating particular areas within the central nervous system, these humoral alterations may well play a major role in the gastrointestinal dysmotility, anorexia, and nausea and vomiting seen in CKD patients (35). Although there is little evidence to suggest that modulation of the actions of endogenous CCK have sustainable regulatory effects on energy intake, antagonists of CCK and its receptors could be considered novel pharmacologic targets for treating vomiting and feeding problems in CKD.
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CONCLUSIONS |
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TOPABSTRACTROLES OF ADIPOKINES IN...ROLE OF GUT HORMONES...CONCLUSIONSREFERENCES |
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, IL-6, IL-1β, leptin,
adiponectin, and resistin may play a significant role. Evidence also suggests
that gut-derived neuropeptides, including ghrelin, PYY, and CCK, may be
important in the pathogenesis of cachexia in ESRD. Further research into the
molecular pathophysiology of these novel hormones in ESRD may lead to novel
therapeutic strategies. |
ACKNOWLEDGMENTS |
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REFERENCES |
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TOPABSTRACTROLES OF ADIPOKINES IN...ROLE OF GUT HORMONES...CONCLUSIONSREFERENCES |
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:
central factors in the altered cytokine network of uremia—the good, the
bad, and the ugly. Kidney Int 2005;67
: 1216-33.[Medline]
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