title: High blood soluble receptor p80 for tumour necrosis factor-alpha is associated with erythropoietin resistance in haemodialysis patients.
abstract: BACKGROUND
  Inflammation is one of the major causes of resistance to erythropoietin (rHuEpo) treatment. Tumour necrosis factor-alpha (TNF-alpha), one of the most potent proinflammatory cytokines, is known to inhibit human erythropoiesis directly in vitro. Although blood levels of soluble receptors for TNF-alpha (sTNFRs) are elevated in haemodialysis (HD) patients, the role of sTNFR for rHuEpo responsiveness in HD patients remains to be clarified.
  
  
  METHODS
  We measured serum sTNFR (p55 and p80) levels in 83 stable outpatients undergoing regular HD (age 62+/-1, HD duration 15+/-1 years). After dividing the patients into three groups according to rHuEpo dose: (low (L) <60, n=31; moderate (M) > or =60 to <120, n=31; high (H) > or =120 U/kg/week rHuEpo, n=21), we examined the relationship between serum sTNFR levels and the degree of renal anaemia and rHuEpo dosage.
  
  
  RESULTS
  Haemoglobin was significantly higher in patients receiving low rHuEpo dosage (L, 10.5+/-0.2; M, 9.7+/-0.1; H, 9.5+/-0.2 g/dl, P<0.01 vs M and H groups). There were no differences in blood TNF-alpha, sTNFR p55, C-reactive protein, albumin, ferritin, or intact parathyroid hormone levels among the three groups. Body mass index and creatinine generation rate, a marker of whole-body muscle volume, were significantly reduced in group H (P<0.01). Serum sTNFR p80 levels were significantly higher in group H (4.88+/-0.45 ng/ml) than in L (3.73+/-0.14 ng/ml) and M (3.67+/-0.21 ng/ml) groups (P<0.05). The blood interleukin (IL)-6 level was also increased in patients requiring high rHuEpo doses (L, 5.5+/-0.5; M, 6.4+/-0.5; H, 10.2+/-2.0 pg/ml, P<0.05 vs L and H groups). A stepwise regression analysis revealed that gender and sTNFR p80 were significant predictors of rHuEpo dosage. A significant direct relationship was found between rHuEpo dose and sTNFR p80 (r=0.499) and IL-6 (r=0.439) values in women (P<0.01) but not in men.
  
  
  CONCLUSIONS
  These findings suggest that high blood sTNFR p80 may contribute to the development of rHuEpo resistance in female patients undergoing long-term HD.
authors.affiliation: First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Kato
authors.forename: M
authors.initials: M
authors.lastname: Odamaki
authors.forename: T
authors.initials: T
authors.lastname: Takita
authors.forename: M
authors.initials: M
authors.lastname: Furuhashi
authors.forename: Y
authors.initials: Y
authors.lastname: Maruyama
authors.forename: A
authors.initials: A
authors.lastname: Hishida
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000097:blood* / Q000378:metabolism; D001769:Blood; D016207:Cytokines / Q000097:blood; D004351:Drug Resistance; D004921:Erythropoietin / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018124:Receptors, Tumor Necrosis Factor / Q000097:blood* / Q000378:metabolism; D047889:Receptors, Tumor Necrosis Factor, Type II; D011994:Recombinant Proteins; D006435:Renal Dialysis; D012727:Sex Characteristics; D012995:Solubility; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D016207:Cytokines; D018124:Receptors, Tumor Necrosis Factor; D047889:Receptors, Tumor Necrosis Factor, Type II; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D004921:Erythropoietin