Effect of circulating soluble receptor for advanced glycation end products (sRAGE) and the proinflammatory RAGE ligand (EN-RAGE, S100A12) on mortality in hemodialysis patients.
OBJECTIVE
The soluble receptor of advanced glycation end products (sRAGE) may exert anti-inflammatory protective roles on the vasculature. In contrast, the RAGE ligand S100A12 (also known as EN-RAGE) contributes to inflammation and the development of atherosclerosis in animal models. Whether alterations at this level contribute to the increased mortality observed in patients on dialysis is currently unknown.


METHODS
Prospective study including 184 prevalent hemodialysis patients and 50 healthy controls matched for age and gender. Plasma concentrations of S100A12 and sRAGE were studied in relation to risk profile and mortality after a median follow-up period of 41 months.


RESULTS
S100A12 and sRAGE levels were significantly elevated in hemodialysis patients compared with healthy controls. S100A12 had a strong positive correlation with C-reactive protein and IL-6, whereas sRAGE negatively associated with C-reactive protein. S100A12, but not sRAGE, was independently and positively associated with clinical cardiovascular disease (CVD). During follow-up, 85 (33 cardiovascular-related) deaths occurred. Whereas sRAGE did not predict mortality, S100A12 was associated with both all-cause (per log(10) ng/ml hazard ratio [HR] 1.93, 95% confidence interval [CI] 1.18 to 3.15) and CVD-related (HR 3.23, 95% CI 1.48 to 7.01) mortality, even after adjustment for age, sex, vintage, and comorbidities. Further adjustment for inflammation made the predictive value of S100A12 disappear for all-cause mortality, but still persisted in CVD-related mortality.


CONCLUSIONS
Circulating S100A12 and sRAGE are both elevated in hemodialysis patients. However, only S100A12 associates with mortality, partly explained by its links with inflammation.
Nakashima
Ayumu
A
Division of Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
Carrero
Juan Jesús
JJ
Qureshi
Abdul Rashid
AR
Miyamoto
Tetsu
T
Anderstam
Björn
B
Bárány
Peter
P
Heimbürger
Olof
O
Stenvinkel
Peter
P
Lindholm
Bengt
B
D002097:C-Reactive Protein / Q000032:analysis; D002318:Cardiovascular Diseases / Q000097:blood; D006801:Humans; D015999:Multivariate Analysis; D011446:Prospective Studies; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000097:blood*; D006435:Renal Dialysis / Q000401:mortality*; D009418:S100 Proteins / Q000097:blood*; D000067616:S100A12 Protein
D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D009418:S100 Proteins; D000067616:S100A12 Protein; C090441:S100A12 protein, human; D002097:C-Reactive Protein