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• W2093008889 abstract "Mortality, malnutrition, and atherosclerosis in ESRD: What is the role of interleukin-6? There is growing evidence that increased plasma concentrations of CRP strongly predict cardiovascular death in both non-renal and renal patient populations. The interleukin-6 (IL-6) system activity, which is the major mediator of the acute phase response, is often markedly up-regulated in uremic patients and has also been shown to predict outcome. This raises the issue of whether or not IL-6 per se may contribute to increased mortality from malnutrition and atherosclerotic cardiovascular disease in uremic patients. The causes of elevated IL-6 levels in the uremic circulation are not fully understood, although a number of factors prevalent in uremic patients, such as hypertension, adiposity, infections, and chronic heart failure may all contribute. However, factors associated with the dialysis procedure, such as bioincompatibility and non-sterile dialysate, may stimulate IL-6 production. Furthermore, available evidence suggests that genetic factors may also have an impact on circulating plasma IL-6 levels. We advance the hypothesis that IL-6 may play a central role in the genesis of inflammatory-driven malnutrition and that it may be regarded as a significant proatherogenic cytokine. This hypothesis may provide a rationale to test if targeted anti-cytokine therapy may be one way to combat the unacceptable high cardiovascular mortality rate among dialysis patients. Mortality, malnutrition, and atherosclerosis in ESRD: What is the role of interleukin-6? There is growing evidence that increased plasma concentrations of CRP strongly predict cardiovascular death in both non-renal and renal patient populations. The interleukin-6 (IL-6) system activity, which is the major mediator of the acute phase response, is often markedly up-regulated in uremic patients and has also been shown to predict outcome. This raises the issue of whether or not IL-6 per se may contribute to increased mortality from malnutrition and atherosclerotic cardiovascular disease in uremic patients. The causes of elevated IL-6 levels in the uremic circulation are not fully understood, although a number of factors prevalent in uremic patients, such as hypertension, adiposity, infections, and chronic heart failure may all contribute. However, factors associated with the dialysis procedure, such as bioincompatibility and non-sterile dialysate, may stimulate IL-6 production. Furthermore, available evidence suggests that genetic factors may also have an impact on circulating plasma IL-6 levels. We advance the hypothesis that IL-6 may play a central role in the genesis of inflammatory-driven malnutrition and that it may be regarded as a significant proatherogenic cytokine. This hypothesis may provide a rationale to test if targeted anti-cytokine therapy may be one way to combat the unacceptable high cardiovascular mortality rate among dialysis patients. Chronic inflammation, as demonstrated by increased levels of various acute phase reactants such as C-reactive protein (CRP), has recently been shown to be a common feature and also to predict outcome and cardiovascular disease in end-stage renal disease (ESRD) patients1.Stenvinkel P. Inflammatory and atherosclerotic interactions in the depleted uremic patient.Blood Purif. 2001; 19: 53-61Crossref PubMed Scopus (172) Google Scholar. Although it is evident that a number of pro- and anti-inflammatory cytokines such as interleukin (IL)-1, IL-10, and tumor necrosis factor-α (TNF-α) as well as soluble cytokine receptors orchestrate the inflammatory response2.Hurst S.M. Wilkinson T.S. McLoughlin R.M. IL-6 and its soluble receptor orchestrate a temporal switch in the pattern of leucocyte recruitment seen during acute inflammation.Immunity. 2001; 14: 705-714https://doi.org/10.1016/S1074-7613(01)00151-0Abstract Full Text Full Text PDF PubMed Scopus (661) Google Scholar, available data suggest that IL-6 plays a key role in these events. IL-6 belongs to a family of 20 kD polypeptide cytokines that are secreted from a number of different cells, including fibroblasts, adipocytes, monocytes and endothelial cells. It is notable that whereas most other cytokines function via paracrine/autocrine mechanisms, the major effects of IL-6 are a consequence of its concentration in the circulation and can take place at sites distinct and far from its origin3.Yudkin J.S. Kumari M. Humphries S.E. Mohamed-Ali V. Inflammation, obesity, stress and coronary heart disease: Is interleukin-6 the link?.Atherosclerosis. 2000; 148: 209-214https://doi.org/10.1016/S0021-9150(99)00463-3Abstract Full Text Full Text PDF PubMed Scopus (1547) Google Scholar. As the hepatic synthesis of CRP is largely under the regulation of IL-6, it is not surprising that the activity of this cytokine is also markedly up-regulated in ESRD patients4.Cavaillon J.M. Pognet J.L. Fitting C. Delons S. Serum interleukin-6 in long-term hemodialysed patients.Nephron. 1992; 60: 307-313Crossref PubMed Scopus (79) Google Scholar, 5.Herbelin A. Urena P. Nguyen A.T. Elevated circulating levels of interleukin-6 in patients with chronic renal failure.Kidney Int. 1991; 39: 954-960Abstract Full Text PDF PubMed Scopus (266) Google Scholar, 6.Kimmel P.L. Phillips T.M. Simmens S.J. Immunologic function and survival in hemodialysis patients.Kidney Int. 1998; 54: 236-244Abstract Full Text Full Text PDF PubMed Scopus (450) Google Scholar. However, although most ESRD patients have elevated IL-6 levels, it should be pointed out that normal or even low plasma levels of IL-6 could be found in dialysis patients, suggesting that genetic factors might be of importance. Indeed, recent findings suggest that certain IL-6 promotor polymorphisms are associated with lower levels of plasma IL-6 in healthy subjects7.Fishman D. Faulds G. Jeffrey R. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis.Circulation. 1998; 102: 1369-1376Google Scholar and peak IL-6 production after coronary artery bypass graft surgery8.Brull D.J. Montgomery H.E. Sanders J. Interleukin-6 gene -174g>c and -572g>c promotor polymorphisms are strong predictors of plasma interleukin-6 levels after coronary artery bypass surgery.Arterioscler Thromb Vasc Biol. 2001; 21: 1458-1463Crossref PubMed Scopus (401) Google Scholar. Since the first report by Bergström et al (abstract; J Am Soc Nephrol 6:573A, 1995) of an association between elevated CRP and outcome, several groups have reported similar findings in both hemodialysis (HD)9.Zimmermann J. Herrlinger S. Pruy A. Inflammation enhances cardiovascular risk and mortality in hemodialysis patients.Kidney Int. 1999; 55: 648-658https://doi.org/10.1046/j.1523-1755.1999.00273.xAbstract Full Text Full Text PDF PubMed Scopus (1411) Google Scholar and peritoneal dialysis (PD)10.Noh H. Lee S.W. Kang S.W. Serum C-reactive protein: A predictor of mortality in continuous ambulatory peritoneal dialysis patients.Nephrol Dial Transplant. 1998; 18: 387-394Google Scholar patients. In view of the strong association between CRP and IL-6, it is not surprising that elevated IL-6 predicts cardiovascular morbidity11.Ridker P.M. Rifai N. Stampfer M.J. Hennekens C.H. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men.Circulation. 2000; 101: 1767-1772Crossref PubMed Scopus (2016) Google Scholar and mortality12.Harris T.B. Ferrucci L. Tracy R.P. Association of elevated interleukin-6 and C-reactive protein levels with mortality in the elderly.Am J Med. 1999; 106: 506-512Abstract Full Text Full Text PDF PubMed Scopus (1268) Google Scholar in non-renal patient groups. A study by Bologa et al13.Bologa R.M. Levine D.M. Parker T.S. Interleukin-6 predicts hypoalbuminemia, hypocholesterolemia, and mortality in hemodialysis patients.Am J Kidney Dis. 1998; 32: 107-114Abstract Full Text Full Text PDF PubMed Scopus (515) Google Scholar has shown that an elevated IL-6 level predicts outcome also in dialysis patients. Similarly, Kimmel et al6.Kimmel P.L. Phillips T.M. Simmens S.J. Immunologic function and survival in hemodialysis patients.Kidney Int. 1998; 54: 236-244Abstract Full Text Full Text PDF PubMed Scopus (450) Google Scholar showed that higher levels of circulating pro-inflammatory cytokines such as IL-6 are associated with mortality, whereas cytokines reflecting improved T-cells function are associated with a survival advantage. In ESRD patients starting dialysis treatment, we similarly observed that elevated IL-6 levels were significantly associated with poor outcome Figure 1. The potential causes of elevated plasma IL-6 levels in ESRD patients are many. Kaizu et al14.Kaizu Y. Kimura M. Yoneyama T. Interleukin-6 may mediate malnutrition in chronic hemodialysis patients.Am J Kidney Dis. 1998; 31: 93-100Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar showed that multiple factors, such as long-term HD, age, and the use of regenerated cellulose membrane dialyzer were associated with elevated IL-6. However, as a recent study showed that IL-6 production does not increase with age per se15.Beharka A.A. Meydani M. Wu D. Interleukin-6 production does not increase with age.J Geront. 2001; 56: B81-88Crossref Scopus (118) Google Scholar, it could be postulated that co-morbid factors associated with age are the main cause of elevated IL-6 levels. Indeed, a number of factors prevalent in ESRD patients, such as chronic heart failure (CHF), high blood pressure, increased body fat mass, insulin resistance, and chronic infections, have recently been shown to be associated with increased IL-6 levels. Because some studies have shown no difference in the circulatory levels of IL-1, IL-6, and TNF-α between long-term and not yet dialyzed patients, this suggests that the uremic syndrome per se may be a more important cause of elevated cytokine levels than the dialysis procedure16.Heberlin A. Urena P. Nguyen A.T. Elevated circulating levels of interleukin-6 in patients with chronic renal failure.Kidney Int. 1991; 39: 954-960Abstract Full Text PDF PubMed Google Scholar,17.Pereira B.J.G. Shapiro L. King A.J. Plasma levels of IL-1β, TNF-α and their specific inhibitors in undialyzed chronic renal failure, CAPD and hemodialysis patients.Kidney Int. 1994; 45: 890-896Abstract Full Text PDF PubMed Scopus (360) Google Scholar. This may partly be caused by the fact that ESRD patients have a lower urinary IL-6 receptor excretion than controls18.Memoli B. Postglione L. Cianciaruso B. Role of different dialysis membranes in the release of interleukin-6 soluble receptor in uremic patients.Kidney Int. 2000; 58: 417-424Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar. Indeed, the deterioration of renal function has been shown to be associated with a significant increase in serum cytokine levels19.Nakanishi I. Moutbarrik A. Okada N. Interleukin-8 in chronic renal failure and dialysis patients.Nephrol Dial Transplant. 1994; 9: 1435-1442PubMed Google Scholar, and a strong positive correlation between creatinine clearance and various cytokines and their soluble receptors has been found in undialyzed patients with varying degree of renal failure20.Descamps-Latscha B. Heberlin A. Nguyen A.T. Balance between IL-1β, TNF-α, and their specific inhibitors in chronic renal failure and maintenance dialysis.J Immunol. 1995; 154: 882-892PubMed Google Scholar. Bolton et al21.Bolton C.H. Downs L.G. Victory J.G.G. Endothelial dysfunction in chronic renal failure: Roles of lipoprotein oxidation and pro-inflammatory cytokines.Nephrol Dial Transplant. 2001; 16: 1189-1197Crossref PubMed Scopus (251) Google Scholar found in a multiple regression analysis that serum creatinine was the sole determinant of IL-6 levels in a group of predialysis and dialysis patients. Similarly, Panichi et al22.Panichi V. Migliori M. De Pietro S. C-reactive protein in patients with chronic renal diseases.Renal Failure. 2001; 23: 551-562Crossref PubMed Scopus (129) Google Scholar recently demonstrated that both CRP and IL-6 levels are related to renal function in predialysis patients. Clinical studies have shown that circulating levels of IL-6 are increased in patients with CHF and that local and systemic effects of pro-inflammatory cytokines may have an important role in the pathogenesis of CHF23.Wollert K.C. Drexler H. The role of interleukin-6 in the failing heart.Heart Failure Rev. 2001; 6: 95-103Crossref PubMed Scopus (163) Google Scholar. It has been reported that changes in IL-6 and CRP are dynamic and that increased levels occur mainly with decompensated CHF24.Sato Y. Takatsu Y. Kataoka K. Serial circulating concentrations of C-reactive protein, interleukin (IL)-4, and IL-6 in patients with acute left heart decompensation.Clin Cardiol. 1999; 22: 811-813Crossref PubMed Scopus (139) Google Scholar. Thus, it is important to distinguish between compensated and decompensated CHF when studying circulatory plasma levels of acute phase reactants and cytokines. As cardiac cachexia is a strong independent risk factor for mortality in non-renal patients with CHF25.Anker S.D. Ponikowski P. Varney S. Wasting as independent risk factor for mortality in chronic heart failure.Lancet. 1997; 349: 1050-1053Abstract Full Text Full Text PDF PubMed Scopus (1125) Google Scholar, it seems conceivable that CHF may contribute to wasting, elevated levels of IL-6, and increased mortality also in ESRD patients. Recently, a significant graded relationship between blood pressure and plasma levels of ICAM-126.Chae C.U. Lee R.T. Rifai N. Ridker P.M. Blood pressure and inflammation in apparently healthy men.Hypertens. 2001; 38: 399-403Crossref PubMed Scopus (570) Google Scholar and IL-626.Chae C.U. Lee R.T. Rifai N. Ridker P.M. Blood pressure and inflammation in apparently healthy men.Hypertens. 2001; 38: 399-403Crossref PubMed Scopus (570) Google Scholar,27.Fernandez-Real J.M. Vayreda M. Richart C. Circulating interleukin 6 levels, blood pressure, and insulin sensitivity in apparently healthy men and women.J Clin Endocrinol Metab. 2001; 86: 1154-1159Crossref PubMed Scopus (412) Google Scholar were observed in apparently healthy subjects. Based on these observations and the documented high prevalence of hypertension in ESRD, it could be speculated that poor blood pressure control might be another factor causing elevated IL-6 levels. Also increased total fat mass may be a cause of elevated IL-6 levels in ESRD patients because production of IL-6 occurs in adipose tissue28.Mohamed-Ali V. Goodrick S. Rawesh A. Subcutaneous adipose tissue releases interleukin-6, but not tumour necrosis factor-α, in vivo.J Clin Endocrin Metab. 1997; 82: 4196-4200Crossref PubMed Google Scholar. As obesity is commonly associated with insulin resistance, it is not surprising that an inverse association between insulin sensitivity and IL-6 has been found27.Fernandez-Real J.M. Vayreda M. Richart C. Circulating interleukin 6 levels, blood pressure, and insulin sensitivity in apparently healthy men and women.J Clin Endocrinol Metab. 2001; 86: 1154-1159Crossref PubMed Scopus (412) Google Scholar. Although accumulating data suggest that various persistent infections, such as Chlamydia pneumoniae, are associated with atherosclerosis, the mechanisms behind this association remain unclear. However, as it recently was demonstrated that the acellular components of Chlamydia pneumoniae are potent stimuli for IL-6 production29.Netea M.G. Selzman C.H. Kullberg B.J. Acellular components of Chlamydia pneumoniae stimulate cytokine production in human blood mononuclear cells.Eur J Immunol. 2000; 30: 541-549Crossref PubMed Scopus (92) Google Scholar, this may be one mechanism by which chlamydial infection causes atherosclerosis. This hypothesis is supported by two recent clinical studies, which showed an association between serological evidence of persistent chlamydial infection, carotid atherosclerosis, and elevated IL-6 levels in ESRD patients, (abstract; Kato et al, J Am Soc Nephrol 12:389A, 2001)30.Stenvinkel P. Heimbürger O. Jogestrand T. Elevated interleukin-6 predicts progressive carotid atherosclerosis in dialysis patients: Association to chlamydia pneumoniae seropositivity.Am J Kidney Dis. 2001Google Scholar. Although Herbelin et al5.Herbelin A. Urena P. Nguyen A.T. Elevated circulating levels of interleukin-6 in patients with chronic renal failure.Kidney Int. 1991; 39: 954-960Abstract Full Text PDF PubMed Scopus (266) Google Scholar found no difference in IL-6 activity between long-term and not yet dialyzed patients, others have found elevated IL-6 levels in dialysis patients compared with ESRD patients not yet on dialysis4.Cavaillon J.M. Pognet J.L. Fitting C. Delons S. Serum interleukin-6 in long-term hemodialysed patients.Nephron. 1992; 60: 307-313Crossref PubMed Scopus (79) Google Scholar,31.Libetta C. De Nicola L. Rampino T. Inflammatory effects of peritoneal dialysis: Evidence of systemic monocyte activation.Kidney Int. 1996; 49: 506-511Abstract Full Text PDF PubMed Scopus (80) Google Scholar. This suggests that the dialysis procedure per se induces an acute inflammatory reaction and generation of IL-6. Indeed, Takahashi et al32.Takahashi T. Kubota M. Nakamura T. Interleukin-6 gene expression in peripheral mononuclear cells from patients undergoing hemodialysis or continuous ambulatory peritoneal dialysis.Renal Failure. 2000; 22: 345-354Crossref PubMed Scopus (37) Google Scholar demonstrated that both HD and PD generate an increase in blood mononuclear cell IL-6 mRNA expression and plasma IL-6 levels. Kaul et al33.Kaul H. Girndt M. Sester U. Initiation of hemodialysis treatment leads to improvement of T-cell activation in patients with end-stage renal disease.Am J Kidney Dis. 2000; 35: 611-616Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar has demonstrated that the initiation of HD leads to a significant improvement of in vitro T-cell function. However, in this study it was notable that the expected normalization of IL-6 production did not occur, which may be the result of cytokine induction of the dialysis membrane33.Kaul H. Girndt M. Sester U. Initiation of hemodialysis treatment leads to improvement of T-cell activation in patients with end-stage renal disease.Am J Kidney Dis. 2000; 35: 611-616Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar. Several factors related to HD have been proposed to contribute to the generation of IL-6 and/or enhance the inflammatory effect of IL-6, dialysis against bioincompatible membrane18.Memoli B. Postglione L. Cianciaruso B. Role of different dialysis membranes in the release of interleukin-6 soluble receptor in uremic patients.Kidney Int. 2000; 58: 417-424Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar, the use of non-sterile dialysate34.Schiffl H. Lang S.M. Stratakis D. Fisher R. Effects of ultrapure dialysis fluid on nutritional status and inflammatory parameters.Nephrol Dial Transplant. 2001; 16: 1863-1869Crossref PubMed Scopus (167) Google Scholar, and backfiltration35.Panichi V. Tetta C. Rindi P. Plasma C-reactive protein is linked to backfiltration associated interleukin-6 production.ASAIO. 1998; 44: M415-M417Crossref PubMed Scopus (47) Google Scholar. There is as yet little available evidence in the literature regarding the effects of PD on the generation of cytokines. However, the systemic inflammatory effects of PD may be similar to those observed in HD as Libetta et al31.Libetta C. De Nicola L. Rampino T. Inflammatory effects of peritoneal dialysis: Evidence of systemic monocyte activation.Kidney Int. 1996; 49: 506-511Abstract Full Text PDF PubMed Scopus (80) Google Scholar found that PD induces activation of monocytes with an enhanced release of IL-6. We (abstract; J Am Soc Nephrol 12:438A, 2001) have recently observed an association between peritoneal transport rate for small solutes and both plasma and intraperitoneal lL-6 levels, suggesting that systemic and intraperitoneal inflammation may be involved in the pathophysiology of high peritoneal transport status in PD patients.Table 1Possible causes of elevated interleukin-6 levels in ESRD patientsFactorReferenceNon-dialysis related factors Hypertension27.Fernandez-Real J.M. Vayreda M. Richart C. Circulating interleukin 6 levels, blood pressure, and insulin sensitivity in apparently healthy men and women.J Clin Endocrinol Metab. 2001; 86: 1154-1159Crossref PubMed Scopus (412) Google Scholar Increased fat mass28.Mohamed-Ali V. Goodrick S. Rawesh A. Subcutaneous adipose tissue releases interleukin-6, but not tumour necrosis factor-α, in vivo.J Clin Endocrin Metab. 1997; 82: 4196-4200Crossref PubMed Google Scholar Insulin resistance27.Fernandez-Real J.M. Vayreda M. Richart C. Circulating interleukin 6 levels, blood pressure, and insulin sensitivity in apparently healthy men and women.J Clin Endocrinol Metab. 2001; 86: 1154-1159Crossref PubMed Scopus (412) Google Scholar Persistent infections (such as chlamydia pneumoniae)29.Netea M.G. Selzman C.H. Kullberg B.J. Acellular components of Chlamydia pneumoniae stimulate cytokine production in human blood mononuclear cells.Eur J Immunol. 2000; 30: 541-549Crossref PubMed Scopus (92) Google Scholar Chronic heart failure24.Sato Y. Takatsu Y. Kataoka K. Serial circulating concentrations of C-reactive protein, interleukin (IL)-4, and IL-6 in patients with acute left heart decompensation.Clin Cardiol. 1999; 22: 811-813Crossref PubMed Scopus (139) Google Scholar Decreased residual renal function21.Bolton C.H. Downs L.G. Victory J.G.G. Endothelial dysfunction in chronic renal failure: Roles of lipoprotein oxidation and pro-inflammatory cytokines.Nephrol Dial Transplant. 2001; 16: 1189-1197Crossref PubMed Scopus (251) Google Scholar,22.Panichi V. Migliori M. De Pietro S. C-reactive protein in patients with chronic renal diseases.Renal Failure. 2001; 23: 551-562Crossref PubMed Scopus (129) Google Scholar Genetic factors7.Fishman D. Faulds G. Jeffrey R. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis.Circulation. 1998; 102: 1369-1376Google ScholarDialysis related factors Bioincompatibility18.Memoli B. Postglione L. Cianciaruso B. Role of different dialysis membranes in the release of interleukin-6 soluble receptor in uremic patients.Kidney Int. 2000; 58: 417-424Abstract Full Text Full Text PDF PubMed Scopus (95) Google Scholar Unpure dialysate34.Schiffl H. Lang S.M. Stratakis D. Fisher R. Effects of ultrapure dialysis fluid on nutritional status and inflammatory parameters.Nephrol Dial Transplant. 2001; 16: 1863-1869Crossref PubMed Scopus (167) Google Scholar Backfiltration35.Panichi V. Tetta C. Rindi P. Plasma C-reactive protein is linked to backfiltration associated interleukin-6 production.ASAIO. 1998; 44: M415-M417Crossref PubMed Scopus (47) Google Scholar Open table in a new tab In the past couple of years, there has been a shift in the general view of the origin of atherosclerosis. The current understanding is that an inflammatory process involving the acute phase response, a biological response to various disturbances such as infection, tissue injury, or immune disturbance, is a primary event36.Ross R. Atherosclerosis: An inflammatory disease.N Engl J Med. 1999; 340: 115-126Crossref PubMed Scopus (19195) Google Scholar. As a recent study has shown that injection of recombinant IL-6 exacerbates early atherosclerosis in apoE-deficient mice, the role of IL-6 in this process may be important37.Huber S.A. Sakkinen P. Conze D. Interleukin-6 exacerbates early atherosclerosis in mice.Arterioscler Thromb Vasc Biol. 1999; 19: 2364-2367Crossref PubMed Scopus (445) Google Scholar. Indeed, several lines of evidence suggest that IL-6 is a significant proatherogenic cytokine. First, elevated levels of IL-6 are a primary stimulant of soluble intercellular adhesion molecule-1 (sICAM-1), which mediates the attachment and migration of leukocytes across the endothelial surface38.Pigott R. Dillon L.P. Hemmingway I.H. Gearing A.J. Soluble forms of E-selectin, ICAM-1 and VCAM-1 are present in the supernatant of cytokine activated cultured endothelial cells.Biochem Biophys Res Commun. 1992; 187: 584-589Crossref PubMed Scopus (639) Google Scholar. We have found a strong positive association between IL-6 and sICAM-1 in ESRD patients supporting this hypothesis Figure 2. Second, IL-6 may contribute to the development of atherosclerosis through various metabolic, endothelial, and coagulant mechanisms recently reviewed by Yudkin et al3.Yudkin J.S. Kumari M. Humphries S.E. Mohamed-Ali V. Inflammation, obesity, stress and coronary heart disease: Is interleukin-6 the link?.Atherosclerosis. 2000; 148: 209-214https://doi.org/10.1016/S0021-9150(99)00463-3Abstract Full Text Full Text PDF PubMed Scopus (1547) Google Scholar. In this respect, it is of interest that both TNF-α and IL-6 inhibit lipoprotein lipase production in adipocyte cell lines39.Greenberg A.S. Nordan R.P. Mcintosh J. Interleukin-6 reduces lipoprotein lipase activity in adipose tissue of mice in vivo and in 3T3–L1 adipocytes: A possible role for interleukin 6 in cancer cachexia.Cancer Res. 1992; 52: 4113-4116PubMed Google Scholar, thus mediating lipolysis and dyslipidemia40.Feingold K.R. Grunfeld C. Role of cytokines in inducing hyperlipidemia.Diabetes. 1992; 41: 97-101Crossref PubMed Google Scholar. Further support for the concept that IL-6 may be more than just a marker of atherosclerosis may be derived from a recent study showing that increased IL-6 expression is involved at the fibrous plaque stage of the atherosclerotic process41.Elhage R. Clamens S. Besnard S. Involvement of interleukin-6 in atherosclerosis but not in the prevention of fatty streak formation by 17beta-estradiol in apolipoprotein E-deficient mice.Atherosclerosis. 2001; 156: 315-320Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar. Finally, a recent clinical study demonstrated that elevated circulating IL-6 levels were independently associated with progressive carotid atherosclerosis during the first 12 months of dialysis treatment30.Stenvinkel P. Heimbürger O. Jogestrand T. Elevated interleukin-6 predicts progressive carotid atherosclerosis in dialysis patients: Association to chlamydia pneumoniae seropositivity.Am J Kidney Dis. 2001Google Scholar. It should be pointed out that other pro-inflammatory cytokines also might affect the atherogenic process. For example, it has been shown that TNF-α may be the key cytokine mediating endothelial dysfunction42.Bhagat K. Vallance P. Inflammatory cytokines impair endothelium-dependent dilatation in human veins in vivo.Circulation. 1997; 96: 3042-3047Crossref PubMed Scopus (368) Google Scholar and in vitro vascular calcification43.Tintut Y. Patel J. Parhami F. Demer L.L. Tumor necrosis factor-α promotes in vitro calcification of vascular cells via the cAMP pathway.Circulation. 2000; 102: 2636-2642Crossref PubMed Scopus (470) Google Scholar. The latter effect of TNF-α could be one possible link in the documented association between inflammation, malnutrition, and cardiac valve calcification recently documented in PD patients44.Wang A.Y.M. Woo J. Wang M. Association of inflammation and malnutrition with cardiac valve calcification in continouous ambulatory peritoneal dialysis patients.J Am Soc Nephrol. 2001; 12: 1927-1936PubMed Google Scholar. It should also be mentioned that various anti-inflammatory cytokines, such as IL-10, might have protective properties in the atherosclerotic process. Girndt et al45.Girndt M. Kohler H. Schiedhelm-Weick E. Production of interleukin-6, tumour necrosis factor alpha and interleukin-10 in vitro correlates with the clinical immune defect in chronic hemodialysis patients.Kidney Int. 1995; 47: 559-565Abstract Full Text PDF PubMed Scopus (164) Google Scholar have postulated that the secretion of IL-10 might be regarded as a compensatory mechanism that controls monokine induction and that patients unable to enhance IL-10 synthesis are at risk. Indeed, Smith et al46.Smith D.A. Irving S.D. Sheldon J. Serum levels of the antiinflammatory cytokine interleukin-10 are decreased in patients with unstable angina.Circulation. 2001; 104: 746-749Crossref PubMed Scopus (240) Google Scholar recently demonstrated that the serum levels of IL-10 are decreased in patients with unstable angina pectoris, and Girndt et al (abstract; J Am Soc Nephrol 12:380A, 2001) have reported that the IL-10 genotype influenced the risk of cardiovascular events in 300 HD patients. Disturbances in protein and energy metabolism, hormonal derangements, and a spontaneous reduction in dietary energy and protein intake may be responsible for the decline in nutritional status with progressive renal failure. Little is known about the specific mechanism(s) responsible for the altered appetite and metabolism in renal disease, although a role for pro-inflammatory cytokines has been proposed47.Plata-Salàman C.R. Cytokines and anorexia: A brief overview.Semin Oncol. 1998; 25: 64-72PubMed Google Scholar. In elderly patients without renal disease, cachexia is usually associated with higher-than-normal concentrations of TNF-α, IL-1, and IL-648.Yeh S.S. Schuster M.W. Geriatric cachexia: The role of cytokines.Am J Clin Nutr. 1999; 70: 183-197PubMed Google Scholar. An important role for IL-6 in this scenario could be proposed, as it stimulates the breakdown of muscle protein49.Goodman M.N. Interleukin-6 induces skeletal muscle protein breakdown in rats.Proc Soc Exp Biol Med. 1994; 205: 182-185Crossref PubMed Scopus (257) Google Scholar, activates cathepsin activity50.Ebisuri C. Tsujinaka T. Morimoto T. Interleukin-6 induces proteolysis by activating intracellular proteases (cathepsin B and L, proteasome) in C2C12 myotubes.Clin Sci. 1995; 89: 431-439Crossref PubMed Scopus (144) Google Scholar, and promotes cancer cachexia51.Strassman G. Fong M. Kenney J.S. Jacob C.O. Evidence for the involvement of interleukin 6 in experimental cancer cachexia.J Clin Invest. 1992; 89: 1681-1684Crossref PubMed Scopus (593) Google Scholar. Moreover, IL-6 receptor antibody has been shown to inhibit muscle atrophy in IL-6 transgenic mice52.Tsujinaka T. Fujita J. Ebisuri C. Interleukin-6 receptor antibody inhibits muscle atrophy and modulates proteolytic systems in interleukin-6 transgenic mice.J Clin Invest. 1996; 97: 244-249Crossref PubMed Scopus (335) Google Scholar. Also, clinical data suggest a significant role for IL-6 in mediating malnutrition in ESRD patients. Increased levels of IL-6 predict hypoalbuminemia13.Bologa R.M. Levine D.M. Parker T.S. Interleukin-6 predicts hypoalbuminemia, hypocholesterolemia, and mortality in hemodialysis patients.Am J Kidney Dis. 1998; 32: 107-114Abstract Full Text Full Text PDF PubMed Scopus (515) Google Scholar,30.Stenvinkel P. Heimbürger O. Jogestrand T. Elevated interleukin-6 predicts progressive carotid atherosclerosis in dialysis patients: Association to chlamydia pneumoniae seropositivity.Am J Kidney Dis. 2001Google Scholar and are associated with various markers of malnutrition in cross-sectional analyses14.Kaizu Y. Kimura M. Yoneyama T. Interleukin-6 may mediate malnutrition in chronic hemodialysis patients.Am J Kidney Dis. 1998; 31: 93-100Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar, 30.Stenvinkel P. Heimbürger O. Jogestrand T. Elevated interleukin-6 predicts progressive carotid atherosclerosis in dialysis patients: Association to chlamydia pneumoniae seropositivity.Am J Kidney Dis. 2001Google Scholar, 53.King A.J. Kehayas J.J. Roubenhoff R. Cytokine production and nutritional status in hemodialysis patients.Int J Artif Org. 1998; 21: 4-11PubMed Google Scholar. Finally, Kaizu et al14.Kaizu Y. Kimura M. Yoneyama T. Interleukin-6 may mediate malnutrition in chronic hemodialysis patients.Am J Kidney Dis. 1998; 31: 93-100Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar showed that the body weight loss over 3 years was significantly higher, and serum albumin levels were significantly lower in dialysis patients with high IL-6 levels. Although pro-inflammatory cytokines may predominantly cause malnutrition by increased protein catabolism, they also affect appetite and eating behavior. The mechanism of cytokine-induced anorexia is not clear, although some studies have implicated a role of elevated leptin. Interestingly, both leptin and its receptor share structural and functional similarities with the IL-6 family of cytokines. Grunfeld et al54.Grunfeld C. Zhao C. Fuller J. Endotoxin and cytokines induce expression of leptin, the ob gene product in hamsters: A role for leptin in the anorexia of infection.J Clin Invest. 1996; 97: 2152-2157Crossref PubMed Scopus (829) Google Scholar found that administration of cytokines increased leptin mRNA levels in hamsters and noted a strong inverse correlation between leptin mRNA level and subsequent food intake. Unfortunately, available data regarding the association between inflammation and leptin are conflicting in humans. Whereas Fouque et al (abstract; J Am Soc Nephrol 12:355A, 2001) have presented data showing a significant positive relation between IL-6 and serum leptin in HD patients, Don et al55.Don B.R. Rosales L.M. Levine N.W. Leptin is a negative acute phase protein in chronic hemodialysis patients.Kidney Int. 2001; 59: 1114-1120Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar demonstrated that leptin levels might actually be suppressed during inflammation. Thus, it is obvious that more studies are needed, especially in humans, to test if pro-inflammatory cytokines mediate anorexia directly at hypothalamic nuclei, indirectly through leptin, or by other mechanisms. As elevated IL-6 levels have a strong predictive power on outcome in ESRD patients and may have direct pro-atherogenic properties, it could be speculated that various treatment strategies inhibiting IL-6 production could decrease cardiovascular morbidity and mortality. For example, Schouten et al56.Schouten W.E.M. Grooteman M.P.C. van Houte A.-J. Effects of dialyser and dialysate on the acute phase response in clinical bicarbonate dialysis.Nephrol Dial Transplant. 2000; 15: 379-384Crossref PubMed Scopus (97) Google Scholar reported that, whereas the use of a bioincompatible dialyzer membrane (Cuprammonium) was associated with increased IL-6 levels, the use of a biocompatible membrane (Polysulfon) was not. Moreover, Schiffl et al34.Schiffl H. Lang S.M. Stratakis D. Fisher R. Effects of ultrapure dialysis fluid on nutritional status and inflammatory parameters.Nephrol Dial Transplant. 2001; 16: 1863-1869Crossref PubMed Scopus (167) Google Scholar have shown that a change from conventional to ultrapure dialysis fluid reduced the levels of IL-6 and improved nutritional status in HD patients. In addition, other treatment regimens, such as ACE-inhibitors57.Gullestad L. Aukrust P. Ueland T. Effect of high- versus low dose angiotensin converting enzyme inhibition on cytokine levels in chronic heart failure.J Am Coll Cardiol. 1999; 34: 2061-2067Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar and vitamin E58.Devaraj S. Jialal I. Alpha tocopherol supplementation decreases serum C-reactive protein and monocyte interleukin-6 levels in normal volunteers and type-2 diabetic patients.Free Radic Biol Med. 2000; 29: 790-792Crossref PubMed Scopus (204) Google Scholar, which have been shown to decrease IL-6 levels in plasma or monocytes in non-renal patient groups, should be considered in ESRD patients. Recently, cytokine-blocking agents, such as monoclonal antibodies, soluble receptors, and receptor antagonists, have been explored as therapeutic agents for patients with rheumatoid arthritis (RA). Injections of anti-IL-6 monoclonal antibodies have been associated with improvement in clinical variables as well as reduced acute-phase protein in RA patients59.Breedweld F.C. Futures trends in the treatment of rheumatoid arthritis: Cytokine targets.Rheumatol. 1999; 38: 11-13Google Scholar. It would therefore be of interest to study the effect of targeted anti-IL-6 treatment on inflammatory and nutritive parameters as well as outcome in ESRD patients. However, as the effects of IL-6 are complex and interrelated to local and systemic concentrations of other pro- and anti-inflammatory cytokines (e.g. TNF-α, IL-1, and IL-10), targeted anti-IL-6 therapy may turn out to have only minor clinical effects. Interleukin-6, the major mediator of the acute phase response, is elevated in most, but not all, ESRD patients and predicts outcome. A number of factors prevalent in patients with ESRD, such as hypertension, adiposity, insulin resistance, CHF, and persistent infections could all be associated with elevated IL-6 levels. However, factors associated with the dialysis procedure, such as bioincompatibility and non-sterile dialysis fluids, also may stimulate IL-6 production. Although patterns of cytokines and their interactions may be more important than individual circulatory plasma levels, we advance the hypothesis that increased IL-6 levels may adversely affect nutritional status and have pro-atherogenic properties in ESRD patients." @default.
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