title: Plasma S100A12 and soluble receptor of advanced glycation end product levels and mortality in chronic kidney disease Stage 5 patients.
abstract: BACKGROUND
  Alterations in the advanced glycation end-products (AGE)-receptor of AGE (RAGE) system are linked to several chronic diseases, which may result from vascular damage. A high circulating level of the pro-inflammatory RAGE-ligand S100A12, also known as EN-RAGE, is thought to promote while a high level of soluble RAGE (sRAGE) is thought to protect against development of atherosclerotic cardiovascular disease (CVD). We evaluated circulating S100A12 and sRAGE in relation to clinical characteristics, nutritional status, inflammation and mortality risk in chronic kidney disease (CKD) Stage 5 patients starting on dialysis.
  
  
  METHODS
  Plasma S100A12 and sRAGE, biomarkers of inflammation and nutritional status, and comorbidities were investigated in 200 CKD Stage 5 patients [median age of 56 years, 62% men and median glomerular filtration rate (GFR) of 6.2 mL/min/1.73 m(2)] in conjunction with initiation of dialysis therapy. Associations between mortality risk and S100A12 or sRAGE were assessed after a median follow-up period of 23 months. In addition, for comparative analyses, S100A12 and sRAGE levels were assessed also in 58 haemodialysis and 78 peritoneal dialysis patients after 1 year of dialysis, 56 CKD Stages 3-4 patients and 50 community-based control subjects.
  
  
  RESULTS
  The median level of S100A12 was 4-fold higher, median sRAGE 2.4 higher and median ratio S100A12/sRAGE 2.27 times higher in CKD 5 patients than in controls. Similar alterations were observed in CKD 3-4 patients; however, CKD 5 patients had a higher median level of sRAGE than the CKD 3-4 patients. In the CKD 5 patients, S100A12 levels were higher in those with diabetes or CVD than in those without these comorbidities. Furthermore, S100A12 correlated with high-sensitivity C-reactive protein (hsCRP) levels (ρ = 0.53; P < 0.001) and a 1-SD higher level of S100A12 associated with increased all-cause mortality risk (hazard ratio 1.32, 95% confidence interval 1.01-1.73) after adjustment for age, sex, comorbidity, nutritional status and inflammation (hsCRP). In the CKD 5 patients, sRAGE correlated negatively with GFR (ρ = -0.26; P < 0.01) but sRAGE did not associate with hsCRP, comorbidities or mortality.
  
  
  CONCLUSIONS
  Plasma concentrations of sRAGE, S100A12 and the ratio S100A12/sRAGE, are markedly elevated in CKD 5 patients starting on dialysis as well as in CKD 3-4 patients and prevalent dialysis patients suggesting that these alterations are typical for patients with moderate or severe CKD. In CKD 5 patients, an increased concentration of S100A12 are associated with inflammation, comorbidities and increased mortality risk whereas no such associations were observed for sRAGE. These results suggest that while high plasma S100A12 is an independent predictor of increased mortality risk, sRAGE does not seem to be a valid risk marker in this patient population.
authors: Divisions of Renal Medicine and Baxter Novum, Karolinska Institutet, Stockholm, Sweden Department of Urology, Yamaguchi University, Ube, Yamaguchi, Japan.
authors: Naohito
authors: N
authors: Isoyama
authors: Divisions of Renal Medicine and Baxter Novum, Karolinska Institutet, Stockholm, Sweden Admiraal de Ruyter Hospital, Goes, The Netherlands.
authors: Paul
authors: P
authors: Leurs
authors: Divisions of Renal Medicine and Baxter Novum, Karolinska Institutet, Stockholm, Sweden.
authors: Abdul Rashid
authors: AR
authors: Qureshi
authors: Divisions of Renal Medicine and Baxter Novum, Karolinska Institutet, Stockholm, Sweden.
authors: Annette
authors: A
authors: Bruchfeld
authors: Divisions of Renal Medicine and Baxter Novum, Karolinska Institutet, Stockholm, Sweden.
authors: Björn
authors: B
authors: Anderstam
authors: Divisions of Renal Medicine and Baxter Novum, Karolinska Institutet, Stockholm, Sweden.
authors: Olof
authors: O
authors: Heimburger
authors: Divisions of Renal Medicine and Baxter Novum, Karolinska Institutet, Stockholm, Sweden.
authors: Peter
authors: P
authors: Bárány
authors: Divisions of Renal Medicine and Baxter Novum, Karolinska Institutet, Stockholm, Sweden.
authors: Peter
authors: P
authors: Stenvinkel
authors: Divisions of Renal Medicine and Baxter Novum, Karolinska Institutet, Stockholm, Sweden.
authors: Bengt
authors: B
authors: Lindholm
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood*; D002097:C-Reactive Protein / Q000032:analysis; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000401:mortality; D008297:Male; D008875:Middle Aged; D010530:Peritoneal Dialysis; D011379:Prognosis; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000097:blood*; D006435:Renal Dialysis; D051436:Renal Insufficiency, Chronic / Q000097:blood / Q000401:mortality*; D009418:S100 Proteins / Q000097:blood*; D000067616:S100A12 Protein; D015996:Survival Rate
chemical_list: D015415:Biomarkers; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D009418:S100 Proteins; D000067616:S100A12 Protein; C090441:S100A12 protein, human; D002097:C-Reactive Protein
keywords: RAGE; cardiovascular disease; end-stage renal disease; inflammation; mortality