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【摘要】
Objective- Receptor for advanced glycation end-products (RAGE) is involved in diabetic vascular complications. We have recently shown that plasma endogenously secretory RAGE (esRAGE), an alternatively spliced form of RAGE, is closely associated with metabolic syndrome and atherosclerosis. Here, we evaluated if plasma esRAGE is a predictor of cardiovascular mortality in a cohort of 206 (171 nondiabetic) patients with end-stage renal diseases (ESRD).
Methods and Results- The cohort was followed for a median of 111 months, and 74 deaths including 34 cardiovascular deaths were recorded. Plasma esRAGE was measured at baseline. Cumulative incidence of cardiovascular death by Kaplan-Meier estimation was significantly higher in subjects in the lowest tertile of plasma esRAGE than those in the middle or the highest tertile both in all and nondiabetic subjects alone. In all subjects, as compared with the lowest tertile of plasma esRAGE, the hazards ratios for the highest and middle tertile were 0.40 (95% CI, 0.18 to 0.89) and 0.26 (0.10 to 0.66), respectively. The higher risk for lower esRAGE was still significant even after adjusted either with body mass index, hypertension, dyslipidemia and vascular complications, but was confounded by age and diabetes.
Conclusions- Low circulating esRAGE is a predictor for cardiovascular mortality in ESRD patients.
Plasma endogenously secretory receptor for AGEs (esRAGE), an alternatively spliced form of RAGE, is closely associated with metabolic syndrome and atherosclerosis. We showed here that low circulating plasma esRAGE is a predictor of cardiovascular mortality in a cohort of 206 patients with end-stage renal diseases.
【关键词】 atherosclerosis cardiovascular mortality end stage renal diseases epidemiology receptor for AGEs risk factors
Introduction
Endogenous nonenzymatic glycoxidation of proteins and lipids leads to the formation of heterogeneous products, collectively termed advanced glycation end-products (AGEs). 1-3 Accumulating evidence suggests that receptor for AGEs (RAGE) is involved in macrovascular complications in diabetes. 4,5 RAGE expression is upregulated in atherosclerotic plaques of diabetic animals. 6 Moreover, augmentation of atherosclerosis in diabetic mice is inhibited by the competition of RAGE with soluble RAGE (sRAGE), lacking the transmembrane and cytoplasmic domains. 6,7
Recently, an endogenous secretory RAGE (esRAGE) has been identified as a novel splice variant carrying all of the extracellular domains but devoid of the transmembrane and intracytoplasmic domains. 8 esRAGE was found to be released outside from the cells, to bind AGEs, and to be capable of neutralizing AGE actions on endothelial cells in culture. 8 In a recent study, we measured circulating human esRAGE level and found that plasma esRAGE was inversely associated with atherosclerosis and metabolic syndrome even in nondiabetic subpopulations. 9 Thus, plasma esRAGE is a potential protective factor against occurrence of cardiovascular diseases.
Patients with end-stage renal disease (ESRD) are known to have several components of metabolic syndrome including insulin resistance 10 and dyslipidemia. 11 Patients with ESRD are also reported to have a substantially elevated cardiovascular mortality rate. 12 In the present study, we performed an observational cohort study in patients with ESRD to evaluate the effect of plasma esRAGE on cardiovascular mortality.
Methods
Study Design and Subjects
The original cohort was described in detail in The MAP ESRD Study that evaluated the effects of metabolic changes on arteriosclerosis and prognosis in ESRD. 13 The present study contains 206 ESRD 3 months at Inoue Hospital, Suita, Japan. The causes of ESRD include 132 chronic glomerulonephritis, 34 diabetic nephropathy, 11 polycystic kidney disease, 6 glomerulosclerosis, 6 systemic lupus erythematosus, 6 eclampsia, 4 chronic pyelonephritis, and 7 unknown. The subjects were recruited from those who were dialyzed in morning sessions, so that blood tests were done after an overnight fast. Table 1 summarizes baseline characteristics of the subjects. Diabetic subgroup was not analyzed in detail because the number of diabetic subjects was too low (n=35, 17.0%). Definition of diabetes mellitus, presence of dyslipidemia, presence of hypertension, and presence of vascular complications was diagnosed as described in detail. 14
TABLE 1. Characteristics of the Cohort
The subjects were registered between June 1992 and June 1995. Mean (±SD) age at entry was 55.6±10.5 years, which was close to the mean age of the entire dialysis population in Japan at the end of 1992 (56.0±13.5 years, N=123 926). They received 3 to 5 hours of hemodialysis, three times per week, using bicarbonate dialysate. They gave informed consent, and this study was approved by the institutional ethical committee.
Blood Sampling and Assays
Blood was drawn in the morning after an overnight fast. Whole blood was used for hematocrit and hemoglobin A1c (HbA1c), EDTA-plasma for esRAGE, pentosidine, glucose, lipids, and serum for other biochemical assays. Plasma esRAGE was measured by enzyme-linked immunosorbent assay as described previously. 9,15 This assay has been developed to specifically measure C-truncated form of RAGE, esRAGE, by using a specific antibody raised against it. Plasma esRAGE levels in healthy subjects appear to be 5-fold less than plasma sRAGE, 9,16 the assay of which uses antibodies raised against full-length RAGE, and detects not only native secretory RAGE but also other soluble forms resulted from the cleavage of cell surface receptor by metalloproteinases. 17 Plasma pentosidine level was measure by enzyme-linked immunosorbent assay. 18 Other measurements were by routine methods.
Outcome Data Collection
The subjects were followed-up to December 2001 with a median follow-up period of 111 (8 to 116) and 116 (8 to 116) months for all and nondiabetic subjects, respectively. Date and cause of death were obtained by reviewing the clinical records. In the cases that moved away to other dialysis units, we reviewed the questionnaire forms filled by the attending physicians at the units. In all subjects, 132 patients were confirmed to be alive on hemodialysis and 74 to be dead at the end of the follow-up. No patients in this cohort were transplanted or changed to peritoneal dialysis during the follow-up period. The 74 deaths during the follow-up included 34 fatal cardiovascular events (8 coronary heart disease, 6 cerebrovascular disease, 10 congestive heart failure, and 10 sudden death). Sudden death was defined as a witnessed death that occurred within 1 hour after the onset of acute symptoms, with no evidence of accident or violence. The 40 fatal noncardiovascular causes were cancer (N=6), infectious disease (N=22), liver disease (N=3), digestive tract disease (N=3), acute pancreatitis (N=1), suicide (N=1), and death of unknown causes (N=4). In nondiabetic subjects (n=171), 50 deaths were recorded at the end of the follow-up, which included 23 fetal cardiovascular (4 coronary heart disease, 4 cerebrovascular disease, 9 congestive heart failure, and 6 sudden death) and 27 noncardiovascular events (5 cancer, 12 infectious disease, 3 liver disease, 2 digestive tract disease, 1 acute pancreatitis, 1 suicide, 3 unknown cause).
Statistical Analysis
Continuous variables were summarized as mean±SD. Median (limits of observed values) was given for plasma esRAGE, duration of hemodialysis, triglycerides, C-reactive protein (CRP), and the follow-up periods because of their skewed distribution. Associations between continuous variables were analyzed by Spearman?s rank correlation test. Comparison of esRAGE between groups was analyzed by Mann-Whitney U test. Survival curves were estimated by the Kaplan-Meier method with log rank test. Prognostic variables for survival were examined using the univariate or multivariable Cox proportional hazards regression models. Probability values less than 0.05 were considered significant. All these analyses were performed using StatView 5 software (SAS Institute Inc, Cary, NC).
Results
Plasma esRAGE Distribution and Its Association With Clinical Parameters
Plasma esRAGE in ESRD patients showed a skewed distribution with a median of 0.558 and 0.606 ng/mL for all and nondiabetic subjects. Similar to nonrenal subjects, 9 diabetic subjects showed significantly lower plasma esRAGE levels than nondiabetic subjects ( P =0.028, Mann-Whitney U test, Table 1 ). Plasma esRAGE was significantly and inversely associated with age, body mass index, triglyceride, and fasting plasma glucose ( Table 2 ). In contrast, plasma esRAGE was positively correlated with high-density lipoprotein (HDL) cholesterol and plasma pentosidine.
TABLE 2. Analysis of the Factors Associated With Plasma esRAGE
Association Between Mortality and Plasma esRAGE
The Figure shows the cumulative incidence of both cardiovascular and non-cardiovascular mortalities of the subjects in the tertiles of plasma esRAGE. The lowest tertile of plasma esRAGE showed significantly higher cardiovascular mortality both in all and in nondiabetic subjects. In contrast, plasma esRAGE was not associated with noncardiovascular mortality in both all and nondiabetic subjects. Univariate Cox proportional hazards analyses in all subjects revealed that, as compared with the subjects in the lowest tertile of plasma esRAGE, those in the middle and the highest tertile had significantly less risk of cardiovascular mortality ( Table 3 ). Similarly in nondiabetic subjects alone, the subjects in the middle and the highest tertile of plasma esRAGE had significantly less cardiovascular mortality than the lowest tertile ( Table 4 ).
Kaplan-Meier curves showing association between plasma esRAGE and cardiovascular mortality. Survival curves in all and non-diabetic subjects were estimated by the Kaplan-Meier method. The lowest, middle, and highest tertile of plasma esRAGE were compared. All subjects: lowest 0.138 to 0.456 ng/mL (n=69), middle 0.458 to 0.746 (n=69), highest 0.753 to 2.49 ng/mL (n=68); nondiabetic subjects: lowest 0.144 to 0.483 (n=57), middle 0.487 to 0.769 (n=57), highest 0.778 to 1.795 (n=57). Probability values were analyzed by log rank test.
TABLE 3. Univariate Association Between Covariates and Mortality by the Cox Proportional Hazards Model in all Subjects
TABLE 4. Univariate Association Between Covariates and Mortality by the Cox Proportional Hazards Model in Nondiabetic Subjects
Univariate Association Between Mortality and Other Clinical Parameters
Table 3 also shows univariate association between mortality and other clinical parameters in all subjects. Besides lowest tertile of plasma esRAGE, higher age, lower serum creatinine, higher non-HDL cholesterol, higher HbA1c, diabetes and vascular complications, were found to be significant univariate predictors of cardiovascular mortality. Similar parameters (lowest tertile of plasma esRAGE, age, lower serum creatinine, higher total cholesterol, higher non-HDL cholesterol, and presence of vascular complications) were identified as significant univariate predictors in non-diabetic subgroup ( Table 4 ). Plasma pentosidine was not associated with cardiovascular mortality both in all and nondiabetic subjects. Significant univariate predictors of noncardiovascular mortality were higher age, lower diastolic blood pressure, lower serum creatinine, lower non-HDL cholesterol, lower serum albumin, higher hematocrit, elevated CRP, male gender, diabetes, and vascular complications in all subjects ( Table 3 ). Similar factors were associated with noncardiovascular mortality in nondiabetic subjects ( Table 4 ).
Low Circulating esRAGE Predicts Cardiovascular Mortality Independent of the Most of the Other Risk Predictors
Multivariable Cox proportional hazards analyses were performed to examine whether the association of low circulating esRAGE with cardiovascular mortality is independent of the other potential confounders ( Table 5 ). The higher risk of the subjects with lower esRAGE was not significant when adjusted with age, fasting plasma glucose or presence of diabetes, suggesting that esRAGE, aging and glycemic control are mutually interacted in the regulation of cardiovascular mortality. Adjustment with other confounders of esRAGE (body mass index, triglyceride, HDL cholesterol, and pentosidine) still resulted in significant higher risk of lower esRAGE ( Table 5 ). Association of lower esRAGE with cardiovascular mortality was independent of the other predictors of cardiovascular mortality (serum creatinine, non-HDL cholesterol, HbA1c, and vascular complications) both in all and in nondiabetic subjects.
TABLE 5. Multivariable Cox Proportional Hazards Models Indicate Low Plasma esRAGE Is An Independent Predictor of Cardiovascular Mortality
Discussion
It?s been proposed that RAGE is deeply involved in diabetic vascular complications. 6,19 Recently, soluble form of RAGE has been shown to be present in the circulation of human, and be hypothesized to act as a decoy receptor for RAGE. 8 Falcone et al 16 measured plasma total sRAGE levels in non-diabetic men, and showed that the levels are significantly lower in patients with coronary artery disease than age-matched healthy controls. We have also recently shown that plasma esRAGE is inversely associated with atherosclerosis in both carotid and femoral arteries as quantitatively determined by ultrasound. 9 In the present report we demonstrate for the first time that reduced circulating esRAGE is a powerful predictor of cardiovascular mortality in a cohort of ESRD patients.
Our recent report suggests that esRAGE is inversely associated with several components of metabolic syndrome. 9 The present report suggests that this story holds true even in patients with ESRD. Thus, inverse association between plasma esRAGE and cardiovascular mortality would be dependent on some of the common risk factors. As expected from close relation among age, diabetes, and RAGE system, inverse association between plasma esRAGE and cardiovascular mortality was not significant when adjusted with diabetes or aging. However, higher cardiovascular risk of subjects with low circulating esRAGE was independent of the other potential confounders including gender, body mass index, blood pressure, and dyslipidemia. Adjustment with other predictors of cardiovascular mortality including creatinine and vascular complications did not affect the relation between lower esRAGE and high cardiovascular mortality.
Currently, 2 types of enzyme-linked immunosorbent assays are available to measure circulating RAGE. One assay is to quantify total sRAGE detecting not only native secretory RAGE but also other soluble forms resulted from the cleavage of cell surface receptor by metalloproteinases. 17 The other immunoassay system that we used in the present study has been developed to specifically measure C-truncated form of RAGE, esRAGE, which could represent part of the sRAGE in human plasma. Indeed, even in ESRD patients, plasma esRAGE (mean level: 0.683 ng/mL) is lower than plasma sRAGE measured in healthy subjects (mean level: 1.335 ng/mL). 16 Because there are no reports comparing these 2 assays in the same subjects, the difference could also represent ethnic differences in esRAGE levels between Japanese and white Italian subjects.
In the general population, low circulating sRAGE has been show to be associated with comorbidity including coronary artery disease, 16 essential hypertension, 20 type 1 diabetes, 15,21 type 2 diabetes, and metabolic syndrome. 9 However, patients with ESRD (median 0.558) showed higher plasma esRAGE levels than subjects without renal diseases (median 0.190). 9 In a preliminary study (n=10), plasma esRAGE level was not significantly different between before (0.550±0.296 ng/mL, mean±SD) and after (0.538±0.276) the single dialysis session ( P =0.926, paired t test), suggesting that esRAGE is not extensively affected by a single dialysis session. Of note, even within the higher range of plasma esRAGE in ESRD patients, the subjects with the lowest tertile of plasma esRAGE are significantly associated with higher incidence of cardiovascular mortality. Potential explanation could be that lack of compensatory increase of plasma esRAGE in renal diseases may be linked to cardiovascular mortality.
AGEs have been implicated not only in diabetic complications but also in insulin resistance 22 and the progression of atherosclerosis as well. 4,5 Some of the recent cohort studies have shown that AGE accumulation (plasma or skin AGE levels) is associated with cardiovascular mortality even in non-diabetic subjects, 23-25 although some controversy remains. 26,27 In the present study, plasma level of pentosidine is significantly and positively associated with plasma esRAGE. However, pentosidine failed to predict cardiovascular mortality in our current cohort. Moreover, association of low circulating esRAGE with cardiovascular mortality was independent of the levels of plasma pentosidine. Thus, association of low circulating esRAGE with cardiovascular mortality may not be strictly through the effect against AGEs.
Atherosclerosis has recently been considered as an inflammatory disease. 28 Metabolic syndrome is also associated with measures of inflammation, such as increased concentrations of CRP. 29,30 Moreover, chronic inflammation has been shown to be an independent predictor of cardiovascular mortality. 31,32 The association between persistent inflammation, AGEs, and RAGE in renal patients was recently described. 33 In population without renal diseases, there is a significant but weak association between esRAGE and serum high-sensitivity CRP. 9 In the present cohort, however, there was no significant correlation between plasma esRAGE and CRP levels. Moreover, esRAGE is still significantly associated with cardiovascular mortality after being adjusted with CRP. Falcone et al also showed that circulating sRAGE levels were independent of CRP. 16 Apparently, further studies are required to examine potential roles of sRAGE in inflammation.
There are a few limitations in this study. First and most importantly, this study is designed to survey the predictors for cardiovascular mortality in the population of ESRD patients, and the number of fatal events was relatively small and statistical power may not be strong enough to detect important cardiovascular risk factors. To prove the role of plasma esRAGE in cardiovascular mortality, further prospective study will be necessary with the required numbers of subjects calculated by the power analysis. Second, evaluating the frequency of cardiovascular diseases in defining the cause of death in ESRD patients could be difficult and may be underestimated. In the present cohort, the risk for all cause mortality of the middle tertile of plasma esRAGE is also significantly less than the lowest tertile (hazards ratio 0.49, 95% confidence interval 0.28 to 0.87). In this article, we confined to cardiovascular mortality simply because all cause mortalities contained quite a few apparent noncardiovascular causes.
In conclusion, the present study revealed that a reduced plasma esRAGE level is a predictor of cardiovascular mortality in a cohort of ESRD patients.
Acknowledgments
The authors thank Masayo Kurato-Monden for technical support.
Sources of Funding
This work was supported by grant-in-aid for scientific research (17590946 to H.K. and H.Y.) from the Japan Society for the Promotion of Science, and the grant from The Osaka Medical Research Foundation for Incurable Diseases (H.K.).
Disclosures
None.
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作者单位：From Department of Metabolism, Endocrinology, and Molecular Medicine (H.K., T.S., S.F., K.S., T.S., M.E., K.M., H.T., Y.N.), Department of Nephrology (E.I.), Osaka City University Graduate School of Medicine, Osaka, Japan; Division of Internal Medicine (R.K., T.T.), Inoue Hospital, Suita, Japan; Dep