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NDT Advance Access originally published online on March 6, 2006
Nephrology Dialysis Transplantation 2006 21(6):1611-1617; doi:10.1093/ndt/gfl053
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Original Articles: Dialysis and Transplantation

Low molecular weight advanced glycation end products predict mortality in asymptomatic patients receiving chronic haemodialysis

Matthew A. Roberts1, Merlin C. Thomas2, Dharsh Fernando3, Neil Macmillan4, David A. Power1 and Francesco L. Ierino1

1 Department of Nephrology, Austin Health, Heidelberg, and Department of Medicine, University of Melbourne, Victoria, 2 Division of Diabetic Complications, Baker Medical Research Institute, Melbourne, 3 Department of Cardiology and 4 Division of Laboratory Medicine, Austin Health, Heidelberg, Victoria, Australia

Correspondence and offprint requests to: Francesco L. Ierino, Department of Nephrology, Austin Health, PO Box 5555, Heidelberg 3084, Victoria, Australia. Email: Frank.IERINO{at}austin.org.au



   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Background. Advanced glycation end products (AGEs) have biological properties that may contribute to the premature cardiovascular mortality of haemodialysis patients. This study examines the hypothesis that low molecular weight forms of fluorescent AGEs (LMW fluorescence) predict mortality in haemodialysis patients.

Methods. The LMW fluorescence was measured in 85 patients treated with chronic haemodialysis and prospectively followed for 4 years. The primary outcome of all-cause mortality was assessed using Cox proportional hazards regression model.

Results. At the end of the follow-up period 37 (44%) patients died. The median LMW fluorescence level was 24.2 arbitrary units (range: 10.6–148.1 AU) and the receiver operator characteristic (ROC) curve cut-off for mortality was 37.0 AU. The LMW fluorescence predicted death both as a binary variable at the ROC cut-off, and as a continuous log-transformed variable when adjusted for age, albumin and C-reactive protein (CRP). Adjusted for age, albumin and CRP, the hazard ratio for mortality was 3.05 (1.41–6.60, P = 0.005) for LMW fluorescence as a binary variable and 2.71 per log unit (1.37–5.38, P = 0.004) as a continuous log-transformed variable.

Conclusion. The low molecular weight forms of AGEs predict mortality in patients receiving chronic haemodialysis, and may be important in the mechanisms leading to atherosclerosis and inflammation in such patients.

Keywords: advanced glycation end products; haemodialysis; mortality



   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Advanced glycation end products (AGEs) contribute to the development and progression of cardiovascular disease [1]. The AGEs are thought to act through receptor-independent and -dependent mechanisms to promote vascular damage, fibrosis and inflammation associated with accelerated atherogenesis [2]. The AGEs and their receptors have been detected within atherosclerotic lesions and correlate with the size and complexity of the lesions [1]. The AGE accumulation is associated with an increase in vascular [3] and cardiac [4] stiffness, and the circulating level of AGEs may be used as a biomarker of tissue AGE accumulation [5].

The production and accumulation of tissue AGEs are increased in patients with end stage renal disease (ESRD), potentially contributing to the observed high mortality in this population. Yet, despite the clear link between renal impairment and the accumulation of AGEs [6], studies in haemodialysis patients have failed to show any association between AGEs and clinically relevant outcomes [7–9]. This observation may be explained by the confounding effect of malnutrition [8]. Malnutrition in dialysis patients increases cardiovascular risk and also reduces circulating protein-bound AGEs via effects on endogenous protein turnover [10] and reduced exogenous AGEs from the diet [11].

Incomplete digestion of AGE-modified protein results in the formation of low molecular weight (LMW) degradation products incorporating AGE modifications. In addition to correlating with tissue AGE modification, LMW AGEs have a high toxic potential, being free to interact with AGE receptors at distant sites via the circulation. Several free AGEs have been identified, including pentosidine, N-(carboxymethyl) lysine (CML) and free-imidazole AGEs. In addition, fluorescence (370 nm [excitation]/440 nm [emission]) in the LMW phase of serum correlates with tissue fluorescence, an established marker for AGE modification [2,5,12]. We have previously demonstrated in patients with type 2 diabetes that LMW fluorescence is correlated with the presence of micro- and macro-vascular complications of disease [6]. This study examines the hypothesis that LMW fluorescence is associated with all-cause mortality in a cross-sectional cohort of patients on haemodialysis, prospectively followed for 4 years.



   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Study population and design
Patients receiving chronic haemodialysis at the Department of Nephrology at Austin Health (Victoria, Australia) were approached to enter the study. Exclusion criteria were poor life expectancy (<6 months) and inability to give informed consent. Ninety-six patients gave written and informed consent and were enrolled into the study. These patients were then followed prospectively for 4 years, during which time they received routine clinical care by physicians blinded to the LMW AGE results. The study was undertaken in conformity with the Declaration of Helsinki, and approved by the Austin Health Human Research Ethics Committee.

Baseline characteristics
At baseline, age, gender, presence or absence of diabetes, history of hypertension, smoking history (any previous smoking) and dyslipidaemia (abnormal lipid profile or taking lipid-lowering agents) were recorded as cardiac risk factors. The use of HMGCoA Reductase Inhibitors (‘statins’) and previous cardiac disease (myocardial infarction, revascularization procedure, or positive diagnostic test for coronary artery disease or left ventricular dysfunction) were also recorded. Haemodialysis variables were obtained from patient records and included time on dialysis, dialysis hours per week and urea reduction ratio (URR) as an index of dialysis quality. Where data was available, adjusted Kt/V was calculated by the Daugirdas formula [13].

Biochemical assays
At baseline, serum samples were collected at the commencement of dialysis on mid-week dialysis days. Samples were stored at –80°C until analysed. Albumin and C-reactive protein (CRP) were measured on non-fasting samples by standard methods (Roche Hitachi 917). Apolipoproteins AI (Apo A) and B (Apo B) were measured by an immunoturbidometric method (Roche Hitachi 917, Mayne Health Dorevitch Pathology, Heidelberg, Victoria). Cardiac troponin I was measured using the AccuTnI assay (Beckman Coulter) on an Access 2 analyser and a level >0.06 µg/l was considered detectable.

The LMW fluorescence was assayed on serum stored at –80°C for 36 months using a previously described method [6], based on an original description by Wrobel et al. [12]. All samples were stored for the same length of time (within a week) and LMW fluorescence is stable in stored samples [14]. Briefly, 20 µl of serum was de-proteinated with 48 µl of trichloroacetic acid and mixed with 10 µl of chloroform. The resulting aqueous phase was injected directly into a carrier stream (deionized water) in which total LMW fluorescence (370/440 nm) was measured using a Waters 470 fluorescence spectrophotometer (Waters, Milford, Massachusetts, US). Injection volume was standardized using the absorbance at 280 nm by an UV detector placed in a series. Samples were processed in duplicate and analysed in triplicate. The content of LMW fluorescence was expressed as arbitrary units (AU) defined by the ratio of the area under the fluorescence curve divided by the area under the absorption curve, normalized to the values derived following exhaustive enzymatic hydrolysis of AGE-modified bovine serum albumin. Using this system, the inter-assay variability was 4% and the inter-day variability was 6%.

Data collection and end-points
After 4 years of follow-up, clinical data were collected by review of medical records and admissions listed on the hospital computer system. The primary endpoint was all-cause mortality. Cardiac death and non-cardiac death were analysed as secondary endpoints. Death was considered cardiac if it followed a myocardial infarction (MI) or witnessed cardiac arrest.

Statistical analysis
We used {chi}2 to analyse dichotomous variables (and Fisher's exact test where expected outcomes were few). A Student's t-test was used to compare means of continuous variables that were normally distributed and Wilcoxon rank sum test was used to compare means of non-parametric data. Normally distributed data are expressed as mean and standard deviation, and non-normally distributed data are expressed as median and inter-quartile range (IQR). A Cox proportional hazards model was used to assess the predictive value of LMW fluorescence. Patients were followed from the date of the serum sample until either death or end of follow-up. Patients were censored at the time of transplant.

Selection of co-variates
Data collected in the study included age and sex, cardiovascular risk factors, dialysis variables and biochemical indices. Because of its skewed distribution, LMW AGE fluorescence was natural log-transformed for the Cox model. In addition, receiver operator characteristic (ROC) analysis was performed to determine the optimum LMW fluorescence cut-point for predicting death. All variables were first analysed as single variables and those that were significant at the P<0.10 level were included in the multivariate analysis. Stepwise backward elimination was used to generate the final model. Each variable in the final model was then tested for interaction with the other variables. Results are expressed as hazard ratios (HRs) with 95% confidence intervals.

Because the sample size limited the number of co-variates that could be included in the model, models were also examined with different selection procedures to test if findings were consistent. Co-variates were also selected if the percentage change in the LMW AGE ß-coefficient was greater than 10% when that variable was added [15], and by the above two methods, but including age, gender, diabetes and previous cardiac disease (variables of clinical relevance to all-cause mortality). The proportional hazards assumption was assessed by examination of scaled Schoenfeld residuals over time and, for categorical variables, inspection of the plots of -ln[-ln(survival)] versus ln(analysis time). Statistical analysis was performed using STATA version 8.2 software (Statacorp, Texas).



   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Baseline characteristics
Ninety-six patients gave consent and four failed to have the baseline blood sample. Stored serum was unavailable in seven. This left 85 patients available for analysis. The baseline characteristics of the 85 haemodialysis patients are shown in Table 1. Seventy-five patients (88%) used Fresenius F7 dialysers (polysulfone), eight (9%) used Fresenius F8 dialysers, and two used high-flux dialysers. Seven patients underwent renal transplantation during the four-year follow-up period.


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  		Table 1. Baseline characteristics of 85 participants. Characteristics are presented as mean±SD, median (inter-quartile range) or number (%)

 
Baseline LMW fluorescence levels
The median LMW fluorescence level was 24.2 AU (range: 10.6–148.1 AU) and the distribution was positively skewed. As previously described in patients with diabetes [5,16], the median LMW fluorescence was lower in men than in women (23.1 vs 29.2, P = 0.002). In addition, patients with hypertension had lower LMW fluorescence (23.7 vs 26.7 in patients without hypertension, P = 0.02). Whilst this may reflect the use of ACE inhibitors and angiotensin receptor blockers in this group, as these agents may independently modify LMW fluorescence [17], the LMW fluorescence was not different between users and non-users of these agents (23.7 vs 24.3 AU, respectively, P = 0.85). The LMW fluorescence was not significantly different between haemodialysis patients with and without diabetes (27.1 vs 24.0, P = 0.64), consistent with previous reports in patients on haemodialysis [16]. Correlation of log-transformed LMW fluorescence was assessed with all continuous variables and the only significant correlation was with apolipoprotein AI (r = 0.25, P = 0.02). Notably, log-transformed LMW fluorescence did not correlate with dialysis indices including URR (r = 0.1, P = 0.37), dialysis vintage (log-transformed, r = 0.12, P = 0.24) or Kt/V (r = 0.13, P = 0.31).

Mortality after four years
After four years, 37 out of 85 patients died (44%). Compared with the survivors, deceased patients were older (64.4±12.1 vs 55.6±16.2 years, P<0.01), and a greater proportion had diabetes (32.4% vs 14.6%, P = 0.05). In addition, they had lower serum albumin (33.2±3.6 g/l vs 36.0±4.0 g/l, P<0.01), higher CRP (14.7 mg/l, IQR 6.7–23.8, vs 5.4 mg/l, IQR 2.6–12.9, P<0.001) and were more likely to have detectable cardiac troponin I at baseline (35.1 vs 14.6%, P = 0.03). However, there was no difference in the proportion with a past history of cardiovascular disease (43.2 vs 41.7%) or in LMW fluorescence levels (24.2 vs 23.9, P = 0.18). The specific causes of death are listed in Table 2.


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  		Table 2. Causes of death as a proportion of all deaths (n = 37)

 
The ROC curve for LMW AGE fluorescence and all-cause mortality is presented in Figure 1. The optimum cut-off was 37.0 AU. Four-year survival was 60% in the patients with LMW AGE fluorescence below the ROC cut-off and 17% in patients with LMW AGE fluorescence above the ROC cut-off (Figure 2). The univariate HRs for each variable suitable for inclusion in the final model (P<0.10) are presented in Table 3, including LMW AGE fluorescence as both the log-transformed continuous variable and dichotomized at the ROC curve determined cut-off value. (HRs for all variables are available as an on-line supplement.) LMW AGE fluorescence above 37 AU more than doubles the hazard of death, but LMW AGE fluorescence was not statistically significant as a log-transformed continuous variable.


Figure 1
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  		Fig. 1. Receiver operator characteristic curve for LMW AGE fluorescence and all-cause mortality.

 

Figure 2
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  		Fig. 2. Survival of patients according to the ROC curve determined cut-off of 37 AU for LMW AGE fluorescence.

 

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  		Table 3. Variables with significant (P<0.10) HRs for all-cause mortality on univariate analysis

 
The multivariate models after backward stepwise elimination incorporating variables listed in Table 3 are presented in Table 4. As a continuous or dichotomous variable, LMW AGE fluorescence remained a strong predictor of mortality adjusted for age, albumin and CRP. The result of the backward stepwise procedure was the same if sex and previous cardiac disease were added to the model. Results were also similar if co-variates were selected based on the percentage change in the LMW AGE fluorescence ß-coefficient, except that age was not included and albumin was removed from Model A (see online supplementary data). Adjustment for use of antagonists of the renin-angiotensin system was also made, but did not alter the final models. Although albumin and CRP were significantly negatively correlated (Pearson's r for log-transformed CRP and albumin = –0.39, P<0.001), there was no interaction between these or other covariates in either model.


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  		Table 4. Multivariate HRs for death using LMW fluorescence as a dichotomous variable in Model A, and a continuous, log-transformed variable in Model B. Both models were initially adjusted for diabetes status and cardiac troponin I, but these were removed in the stepwise elimination procedure

 
Secondary outcomes
Analysis of cardiac (n = 10) and non-cardiac (n = 27) deaths was undertaken. The LMW AGE fluorescence dichotomized at the ROC curve cut-off was a significant predictor of cardiac death on univariate analysis, with an HR of 4.9 (1.4–17.5, P = 0.014). However, there were too few events for a multivariate Cox regression analysis of these outcomes to be performed.



   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
Advanced glycation end products and their receptors are viewed as having a pivotal role in the initiation and progression of cardiovascular disease [18]. This 4 year prospective study demonstrates that LMW fluorescence, a biomarker of tissue AGE accumulation [5], is associated with mortality in patients on haemodialysis. This finding is consistent with the potential role of AGEs as ‘middle molecule’ uraemic toxins in patients with ESRD and adds LMW fluorescence to the list of other biochemical markers of risk in ESRD such as the cardiac troponins [19] and CRP [20], both of which also predicted adverse outcome in this study.

These results are in contrast to previous studies in haemodialysis patients, which failed to show any association between AGEs and mortality [7–9]. An important difference between these studies and the present study is that the LMW fraction of AGEs in serum was analysed rather than the protein-linked high molecular weight AGEs measured in other studies. Fluorescence in the LMW fraction of serum is elevated in haemodialysis patients [16], and the current study confirms this, with 3-fold higher levels in patients on haemodialysis than healthy control patients with normal renal function using this same assay (previously reported as 7.0 AU) [6]. LMW AGEs form from the incomplete digestion of AGE-modified protein, with the LMW degradation products incorporating AGE modifications. These accumulate in the circulation of patients with ESRD because of both increased generation of glycoxidative intermediates and impaired renal clearance of exogenous and endogenous adducts.

Although the molecular identity of putative fluorophores remains to be established, there is strong evidence linking fluorescence measures to both AGE accumulation and its functional corollary. For example, collagen becomes proportionally more fluorescent and less soluble with age [21]. N{epsilon}-(carboxymethyl) lysine (CML) is a non-fluorescent AGE, and non-CML AGEs correlate better with complications in patients with type 1 diabetes [22]. Treatments that reduce the accumulation of tissue AGE fluorescence are also protective against the development of diabetic complications [1]. Therefore, LMW fluorescence should be considered as a biomarker of tissue amine modification linked to the presence of (unmeasured) toxic molecules with cross-linking potential or the ability to activate specific AGE receptors.

A number of mechanisms by which LMW AGE accumulation might contribute to complications of haemodialysis have been proposed. Indeed, LMW AGEs may have a higher toxic potential than those of larger AGE-modified proteins, being free to interact with AGE receptors at distant sites via the circulation [5]. Both in vitro and in vivo, AGE-adducts are able to activate endothelial cells and mononuclear phagocytes, triggering the production of pro-inflammatory and fibrogenic cytokines, chemokines and growth factors in the vessel wall [18]. Endothelial cells may also react with AGEs to promote cell adhesion, transendothelial migration, inflammation and the formation of blood clots [23]. The AGEs also have a number of actions independent of receptor activation, including direct actions on oxidative stress and the quenching of NO. In addition, AGE peptides isolated from serum can react covalently with other proteins, such as Apo B, resulting in significant changes in both structure and function [24].

In our study, the association between LMW fluorescence and mortality was significant for LMW AGE fluorescence dichotomized at the ROC cut-off but not as a log-transformed continuous variable. However, when adjusted for age, serum albumin and CRP, LMW AGE fluorescence became a strong independent predictor of death as a continuous or binary variable. Overall, serum albumin had the greatest influence on this relationship as demonstrated by the effect on the LMW fluorescence ß-coefficient (see online supplementary data). Several factors may affect metabolism of serum proteins in haemodialysis patients, including nutritional status, inflammation, metabolic acidosis and dialysis modality. These in turn may affect the measurement of circulating AGE-modified protein in this cohort, as these factors lead to increased protein turnover [10]. This association between AGEs and nutritional status is important because, the diet is a major source of AGEs in patients on dialysis and diets low in AGEs have been shown to reduce circulating AGE levels in these patients [11]. Reduced protein and calorie intake associated with uraemia may represent a protective mechanism in CKD, whereby a spontaneous reduction in protein intake acts to reduce exposure to dietary AGEs, and therein AGE-related toxicity.

The sample size of our study imposes limitations with regard to the number of variables we can include in the multivariate analysis. Because of a concern that the results may differ with different co-variates in the model, we evaluated variables based on two different criteria (univariate P<0.10 and >10% change in LMW AGE fluorescence ß-coefficient). In both cases, the LMW AGE fluorescence remained an important predictor. The lack of association of previous cardiovascular disease with death in this study probably reflects both the lower frequency of cardiac causes of death in this study (27%) and possible underestimation of the presence of cardiovascular disease at baseline.

Given the association between AGEs and outcomes, interventions to specifically reduce AGE accumulation in patients on haemodialysis may one day be considered as a component of standard clinical practice. Measures to reduce exposure of the peritoneum to excessive amounts of AGEs already form a useful part of peritoneal dialysis therapy. Reduction in circulating AGEs can be achieved through dietary modifications in patients on dialysis [11]. Dialysis itself is not sufficient to remove ‘middle molecule’ toxins such as AGEs, as suggested by the lack of association between LMW fluorescence and URR or Kt/V. Alternative dialytic strategies such as haemodialysis with a high-flux and super-flux dialysers and totally or partially convective treatments may also have particular utility [25]. The usefulness of drugs that specifically reduce AGE accumulation in patients on haemodialysis remains to be established. However, it should be noted that both ACE inhibitors and angiotensin receptor blockers have anti-AGE effects that may contribute to their particular efficacy in patients with ERSD [17,26].

In conclusion, this study demonstrates, for the first time, an association between LMW fluorescence and mortality in patients on haemodialysis, particularly when adjusted for serum albumin, CRP and patient age. Future studies testing the utility of interventions to specifically reduce AGE accumulation in patients on dialysis are keenly awaited.



   Acknowledgments
 
We thank the dialysis nursing staff for collecting multiple serum samples, in particular Cathy Chan and Steven Brown. Shorter follow-up of this work was presented in abstract form at the Australia and New Zealand Society of Nephrology, and American Society of Nephrology Annual Scientific Meetings in 2004. M.A.R. is the recipient of a National Health and Medical Research Council (NHMRC) Postgraduate Research Scholarship (310632) for 2004–2005, and a NHMRC Centre for Clinical Research Excellence in Renal Medicine Scholarship for the study of Clinical Epidemiology in 2004.

Conflict of interest statement. None declared.



   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Received for publication: 19. 9.05
Accepted in revised form: 31. 1.06


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