This study followed-up 550 patients on maintenance hemodialysis after measurement of their plasma S100A12 levels. The main findings of the present study are as follows. A higher plasma S100A12 level (≥18.79 ng/mL) in hemodialysis patients was a significant predictor of the two-year all-cause mortality. In addition to the plasma S100A12 levels, age ≥65 years, serum albumin levels <3.5 g/dL, and a history of CVD were independent predictors of the two-year all-cause mortality. The predicting integer score developed using these four factors provided statistically significant information. Finally, external validation in a cohort of 303 hemodialysis patients at an independent center demonstrated that the simple integer score proposed here provided good discriminative power, and therefore serves as a useful predictive model of mortality in hemodialysis patients.
Prolonged subclinical inflammation causes release of intracellular molecules that alert the immune system to danger. Recent studies reported that these endogenous damage-associated molecular pattern (DAMP) molecules or alarmins, which are released from necrotic cells and activated leucocytes, play a crucial role in the inflammatory response . Examples of putative DAMPs include endogenous RAGE ligands such as high-mobility group box 1 and S100 proteins (S100A8/A9 and S100A12), interleukins (IL) such as IL-1α, heat-shock proteins, and nucleosome . The S100A12 expression is high in inflammatory diseases such as rheumatoid arthritis, Crohn’s disease, Kawasaki disease, and atherosclerosis [28–31]. Atherosclerosis, which causes CVD, is also characterized by the presence of subclinical chronic inflammation . Furthermore, abnormal persistence of DAMPs in chronic inflammation and in tumor microenvironments is associated with carcinogenesis . Signals that activate RAGE, which is also regarded as a prototypic DAMP receptor, may trigger a positive regulatory loop that maintains the inflammatory microenvironment required for the promotion of tumor development . Thus, the interaction of S100A12 with RAGE may be involved in diverse processes such as inflammatory-induced atherosclerosis, defense against infection, and tumorigenesis. These factors contribute to the all-cause mortality in hemodialysis patients; thus, measurement of S100A12 levels may provide a sensitive discriminative predictor.
Two observational studies have been conducted examining the relationship between mortality and S100A12 in hemodialysis patients. Nakashima et al.  performed an ad hoc analysis of 184 prevalent hemodialysis patients in Sweden. They showed that the S100A12 level was an independent predictor of the all-cause and CVD-related mortality. Adjustment for plasma IL-6 levels as an inflammatory marker significantly attenuated the association with the all-cause mortality but not with respect to cardiovascular mortality. Because plasma IL-6 levels were not measured in this larger prospective study, a direct comparison with the results of the Swedish study was not possible. The low mortality rate in the current study (9%) did not allow statistical evaluation of the function of each cause of death, probably because of differences in the circumstances between dialysis facilities. Very recently, a prospective study of 261 Czech hemodialysis patients by Kalousova et al.  found a relationship between S100A12 levels and infection-related mortality. In contrast to the present study and the Swedish study, they found no difference between baseline S100A12 levels in the hemodialysis patients and those of healthy controls. In addition, interstitial nephritis and polycystic kidney disease were present in 26.8% and 14.6% of patients in that study, respectively; these values differed significantly from those in our subjects. Therefore, direct comparison between their study results and those of the current study was difficult. However, the relationship between mortality due to infection and S100A12 should be considered.
The risk scoring system developed in this study, which included the plasma S100A12 levels, was useful in predicting the two-year all-cause mortality. A score of 0–4 was calculated using data for age, albumin levels, history of CVD, and S100A12 levels derived from analysis of 550 participants. This score successfully predicted mortality even in the validation population. Furthermore, this simple model, which requires no extensive computation, can be used in clinical settings for rapid evaluation of the patient status. Considering the risk stratification and planning involved in the management of hemodialysis patients, this score system may provide useful and meaningful information to practitioners. Because the population of hemodialysis patients is increasing and because of economic and medical staff limitations, intensive treatment of all the patients who received maintenance hemodialysis is not possible [33, 34]. For hemodialysis patients at high risk according to our proposed scoring system, a strong intention to treat, such as more careful observation of patient status; and shorter intervals between imaging studies to screen for CVD, malignancy, and infectious disease are recommended. In this context, the proposed scoring system may be a useful risk stratification tool in clinical settings. Prospective verification of the clinical usefulness of this system in our affiliated clinics is planned in future.
Some limitations of the present study must be acknowledged. First, prevalent but not incident dialysis patients were selected for inclusion. Second, although the sample size analyzed here was larger than that in previous studies performed in Sweden and Czech Republic [16, 17] on the relationship between S100A12 levels and mortality in hemodialysis patients, the total number of deaths in this Japanese study was small. However, one report suggested that clinical prognosis is better in Japanese hemodialysis patients compared with those in other countries . Third, other possible risk factors for mortality in ESRD patients, such as vascular calcification, nutritional state, subjective comorbid score, levels of candidate markers (brain natriuretic peptide, fetuin-A, and IL-6), dialysis adequacy, and residual renal function may be important, but were not measured here. Finally, the diagnostic assays currently used for measurement of S100A12 levels are useful for research purposes only. To date, no commercially available routine tests have become available for determining S100A12 levels in clinical studies. In addition, normal and reference plasma values are still under debate.