Patients on hemodialysis (HD) have a high burden of chronic inflammation induced associated with multiple comorbidities including poor nutritional status. Endotoxin (ET) is a Gram-negative bacterial cell wall component and a potent stimulus for innate immune system activation leading to the transcription of proinflammatory cytokines (e.g., IL-1, IL-6, and TNFα) that adversely affect protein metabolism and nutrition. Several cross-sectional observational studies have found that elevated serum ET concentrations in hemodialysis patients are associated with lower serum albumin, higher proinflammatory cytokine, and C-reactive protein concentrations. Possible sources of ET in the systemic circulation are bacterial translocation from the gastrointestinal tract and iron supplementation, potentially leading to intestinal bacterial overgrowth. Sevelamer is a nonabsorbable hydrogel approved for use as a phosphate binder in HD patients. Reductions in serum ET concentrations in hemodialysis patients have been observed with sevelamer therapy in observational studies and the few published interventional studies. Reduction of ET concentrations was associated with concomitant reductions in TNFα, IL-6, and CRP and improvement in serum albumin in the majority of these small studies. Additional studies are needed to evaluate the potential effects of sevelamer treatment on nutritional status in chronic kidney disease (CKD) patients with elevated ET. 1. Introduction Proinflammatory cytokines such as IL-1, IL-6, and TNF- and the anti-inflammatory cytokine IL-10 are elevated in hemodialysis (HD) patients . Several factors are linked with the Proinflammatory state in end-stage renal disease (ESRD) patients on dialysis including nutritional status, diabetes, hypertension, sepsis, and biocompatibility with dialysis membranes . Poor nutritional status is a vexing clinical problem that occurs in up to 50% of ESRD patients on hemodialysis and is associated with increased mortality . Documented appetite loss in ESRD patients is associated with higher mortality rates . Albumin is a negative acute phase reactant, and low serum albumin concentrations are associated with elevated markers of inflammation including IL-6, CRP, and TNF- [4–6]. ESRD patients on HD exhibit increased protein catabolism profiles and greater skeletal muscle breakdown that is correlated with reduced serum albumin concentrations [5, 7, 8]. This loss of lean body mass in concert with chronic inflammation has been identified as a major risk factor for cardiac heart failure in ESRD patients [9, 10].
T. A. Ikizler, R. L. Wingard, J. Harvell, Y. Shyr, and R. M. Hakim, “Association of morbidity with markers of nutrition and inflammation in chronic hemodialysis patients: a prospective study,” Kidney International, vol. 55, no. 5, pp. 1945–1951, 1999.
J. J. Carrero, A. R. Qureshi, J. Axelsson et al., “Comparison of nutritional and inflammatory markers in dialysis patients with reduced appetite,” The American Journal of Clinical Nutrition, vol. 85, no. 3, pp. 695–701, 2007.
D. S. Raj, J. J. Carrero, V. O. Shah et al., “Soluble CD14 Levels, Interleukin 6, and mortality among prevalent hemodialysis patients,” The American Journal of Kidney Diseases, vol. 54, no. 6, pp. 1072–1080, 2009.
K. Kalantar-Zadeh, G. Block, C. J. McAllister, M. H. Humphreys, and J. D. Kopple, “Appetite and inflammation, nutrition, anemia, and clinical outcome in hemodialysis patients,” The American Journal of Clinical Nutrition, vol. 80, no. 2, pp. 299–307, 2004.
T. A. Ikizler, L. B. Pupim, J. R. Brouillette et al., “Hemodialysis stimulates muscle and whole body protein loss and alters substrate oxidation,” The American Journal of Physiology, vol. 282, no. 1, pp. E107–E116, 2002.
F. D. Vannini, A. A. Antunes, J. C. T. Caramori, L. C. Martin, and P. Barretti, “Associations between nutritional markers and inflammation in hemodialysis patients,” International Urology and Nephrology, vol. 41, no. 4, pp. 1003–1009, 2009.
C. W. McIntyre, L. E. A. Harrison, M. T. Eldehni et al., “Circulating endotoxemia: a novel factor in systemic inflammation and cardiovascular disease in chronic kidney disease,” Clinical Journal of the American Society of Nephrology, vol. 6, no. 1, pp. 133–141, 2011.
P. Y. Hsu, C. L. Lin, C. C. Yu et al., “Ultrapure dialysate improves iron utilization and erythropoietin response in chronic hemodialysis patients: a prospective cross-over study,” Journal of Nephrology, vol. 17, no. 5, pp. 693–700, 2004.
U. Feroze, K. Kalantar-Zadeh, K. A. Sterling et al., “Examining associations of circulating endotoxin with nutritional status, inflammation, and mortality in hemodialysis patients,” Journal of Renal Nutrition, vol. 22, no. 3, pp. 317–326, 2012.
S. Genth-Zotz, S. von Haehling, A. P. Bolger et al., “Pathophysiologic quantities of endotoxin-induced tumor necrosis factor-alpha release in whole blood from patients with chronic heart failure,” The American Journal of Cardiology, vol. 90, no. 11, pp. 1226–1230, 2002.
S. Gonclaves, R. Pecoits-Filho, and S. Perreto, “Fluid overload is associated with endotoxinemia but not with systemic inflammation in chronic kidney disease patients,” Journal of the American Society of Nephrology, vol. 16, p. 470A, 2005.
P. P. Sun, M. C. Perianayagam, and B. L. Jaber, “Sevelamer hydrochloride use and circulating endotoxin in hemodialysis patients: a pilot cross-sectional study,” Journal of Renal Nutrition, vol. 19, no. 5, pp. 432–438, 2009.
E. S. van Amersfoort, T. J. C. van Berkel, and J. Kuiper, “Receptors, mediators, and mechanisms involved in bacterial sepsis and septic shock,” Clinical Microbiology Reviews, vol. 16, no. 3, pp. 379–414, 2003.
A. B. Hauser, I. R. F. Azevedo, S. Gon？alves, A. Stinghen, C. Aita, and R. Pecoits-Filho, “Sevelamer carbonate reduces inflammation and endotoxemia in an animal model of uremia,” Blood Purification, vol. 30, no. 3, pp. 153–158, 2010.
N. Noori, C. P. Kovesdy, R. Dukkipati et al., “Racial and ethnic differences in mortality of hemodialysis patients: role of dietary and nutritional status and inflammation,” The American Journal of Nephrology, vol. 33, no. 2, pp. 157–167, 2011.
K. A. Powers, A. Kapus, R. G. Khadaroo, G. Papia, and O. D. Rotstein, “25% albumin modulates adhesive interactions between neutrophils and the endothelium following shock/resuscitation,” Surgery, vol. 132, no. 2, pp. 391–398, 2002.
H. Kitano, H. Fukui, Y. Okamoto et al., “Role of albumin and high-density lipoprotein as endotoxin-binding proteins in rats with acute and chronic alcohol loading,” Alcoholism Clinical and Experimental Research, vol. 20, no. 1, supplement, pp. 73A–76A, 1996.
P. Kotanko, M. Carter, and N. W. Levin, “Intestinal bacterial microflora—a potential source of chronic inflammation in patients with chronic kidney disease,” Nephrology Dialysis Transplantation, vol. 21, no. 8, pp. 2057–2060, 2006.
J. R. Boelaert, R. F. Daniels, M. L. Schurgers, E. G. Matthys, B. Z. Gordts, and H. W. van Landuyt, “Iron overload in haemodialysis patients increases the risk of bacteraemia: a prospective study,” Nephrology Dialysis Transplantation, vol. 5, no. 2, pp. 130–134, 1990.
A. B. Pai, J. Depczynski, M. P. Pai, C. R. McQuade, and R. C. Mercier, “Non-transferrin-bound iron is associated with enhanced Staphylococcus aureus growth in hemodialysis patients receiving intravenous iron sucrose,” The American Journal of Nephrology, vol. 26, no. 3, pp. 304–309, 2006.
D. S. C. Raj, V. O. Shah, M. Rambod, C. P. Kovesdy, and K. Kalantar-Zadeh, “Association of soluble endotoxin receptor CD14 and mortality among patients undergoing hemodialysis,” The American Journal of Kidney Diseases, vol. 54, no. 6, pp. 1062–1071, 2009.
H. Terawaki, K. Yokoyama, Y. Yamada et al., “Low-grade endotoxemia contributes to chronic inflammation in hemodialysis patients: examination with a novel lipopolysaccharide detection method,” Therapeutic Apheresis and Dialysis, vol. 14, no. 5, pp. 477–482, 2010.
O. Wrong and C. Harland, “Sevelamer and other anion-exchange resins in the prevention and treatment of hyperphosphataemia in chronic renal failure,” Nephron Physiology, vol. 107, no. 1, pp. 17–33, 2007.
V. Autissier, S. J. P. Damment, and R. A. Henderson, “Relative in vitro efficacy of the phosphate binders lanthanum carbonate and sevelamer hydrochloride,” Journal of Pharmaceutical Sciences, vol. 96, no. 10, pp. 2818–2827, 2007.
J. F. Navarro-González, C. Mora-Fernández, M. M. de Fuentes, J. Donate-Correa, V. Caza？a-Pérez, and J. García-Pérez, “Effect of phosphate binders on serum inflammatory profile, soluble CD14, and endotoxin levels in hemodialysis patients,” Clinical Journal of the American Society of Nephrology, vol. 6, no. 9, pp. 2272–2279, 2011.
H. Vlassara, J. Uribarri, W. Cai et al., “Effects of sevelamer on HbA1c, inflammation, and advanced glycation end products in diabetic kidney disease,” Clinical Journal of the American Society of Nephrology, vol. 7, no. 6, pp. 934–942, 2012.
W. N. Suki, “Effects of sevelamer and calcium-based phosphate binders on mortality in hemodialysis patients: results of a randomized clinical trial,” Journal of Renal Nutrition, vol. 18, no. 1, pp. 91–98, 2008.
B. Di Iorio, A Bellasi, and D. Russo, “Mortality in kidney disease patients treated with phosphate binders: a randomized study,” Clinical Journal of the American Society of Nephrology, vol. 7, no. 3, pp. 487–493, 2012.