Skin Autofluorescence, a Measure of Cumulative Metabolic Stress and Advanced Glycation End Products, Predicts Mortality in Hemodialysis Patients
Robbert Meerwaldt*,
Jasper W.L. Hartog*,
Reindert Graaff,
Roel J. Huisman,
Thera P. Links*,
Nynke C. den Hollander*,
Susan R. Thorpe,
John W. Baynes,
Gerjan Navis*,
Rijk O.B. Gans* and
Andries J. Smit*
Departments of * Medicine and Biomedical Engineering University Medical Center Groningen, University of Groningen, and Dialysis Center Groningen, Groningen, the Netherlands; and Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina
Address correspondence to: Dr. Robbert Meerwaldt, University Medical Center Groningen, Department of Medicine U3.129, Hanzeplein 1, Groningen 9700 RB, The Netherlands. Phone: +31-50-3616161; Fax: +31-50-3619069; E-mail: r.meerwaldt{at}isala.nl
Received for publication February 5, 2005.
Accepted for publication September 27, 2005.
Tissue advanced glycation end products (AGE) are a measure ofcumulative metabolic stress and trigger cytokines driven inflammatoryreactions. AGE are thought to contribute to the chronic complicationsof diabetes and ESRD. Tissue autofluorescence is related tothe accumulation of AGE. Therefore, skin autofluorescence (AF)may provide prognostic information on mortality in hemodialysis(HD) patients. Skin AF was measured noninvasively with an AFreader at baseline in 109 HD patients. Overall and cardiovascularmortality was monitored prospectively during a period of 3 yr.The AF reader was validated against AGE contents in skin biopsiesfrom 29 dialysis patients. Forty-two of the 109 (38.5%) HD patientsdied. Cox regression analysis showed that AF was an independentpredictor of overall and cardiovascular mortality (for overallmortality odds ratio [OR] 3.9), as were pre-existing cardiovasculardisease (CVD; OR 3.1), C-reactive protein (OR 1.1), and serumalbumin (OR 0.3). Multivariate analysis revealed that 65% ofthe variance in AF could be attributed to the independent effectsof age, dialysis and renal failure duration, presence of diabetes,triglycerides levels, and C-reactive protein. AF was also independentlylinked to the presence of CVD at baseline (OR 8.8; P < 0.001).AF correlated with collagen-linked fluorescence (r = 0.71, P< 0.001), pentosidine (r = 0.75, P < 0.001), and carboxy(m)ethyllysine(both r = 0.45, P < 0.01). Skin AF is a strong and independentpredictor of mortality in ESRD. This supports a role for AGEas a contributor to mortality and CVD and warrants interventionsspecifically aimed at AGE accumulation.
The increased accumulation of tissue advanced glycation endproducts (AGE) is a series of complex and sequential reactions,collectively called the Maillard reaction. AGE accumulationresults from a combination of hyperglycemia, oxidative/carbonylstress, and/or decreased renal clearance of AGE precursors (1–4).Hyperglycemia is a sufficient but not necessary condition forincreased AGE formation. AGE are significantly increased inuremia, even in the absence of hyperglycemia (1). Accumulationof chemically stable AGE on long-lived proteins may serve asa measure of cumulative metabolic stress (5–7) and affectsthe structure and function of proteins, enhances cytokine production,and activates transcription factors via binding to specificreceptors (e.g., receptor for AGE) (8).
Because of their biochemical characteristics, AGE have beenimplicated as a contributing factor in the progression of chronic,age-related diseases, such as atherosclerosis, ESRD, and diabetes(1,3,8–11). In a substudy of the Diabetes Control andComplications Trial, skin AGE levels explained a major partof the variance in diabetic complications, even after adjustmentfor glycosylated hemoglobin (HbA1c) (12). Inhibition of AGEaccumulation experimentally reduces the development of severaldiabetic complications (13–15). In ESRD, AGE accumulationhas been linked to accelerated atherosclerosis, even in euglycemicpatients (16–18). Cooper and colleagues (19,20) reportedthat ACE inhibitors and angiotensin receptor blockers also inhibitAGE formation in animal models of diabetes, further implicatingAGE as a biomarker or causative factor in the development ofdiabetic nephropathy.
The influence of tissue AGE accumulation on survival in diabetesand ESRD is yet unknown. Determination of tissue AGE accumulationis an invasive, expensive procedure, and blood and urine samplingof AGE does not necessarily reflect tissue AGE (21). However,tissue autofluorescence (AF) has been related to the accumulationof AGE and to the progression of chronic complications of diabetesand ESRD (22). Recently, we described a noninvasive opticaltool, the AF reader (AFR), for measuring skin AF (23). SkinAF seemed to be related strongly to collagen-linked fluorescence,pentosidine and carboxy(m)ethyllysine (CML and CEL) accumulation(23) and to long-term complications in patients with diabetes(24).
Mortality rates in hemodialysis (HD) patients are markedly increased,despite measures to improve survival (25). Cardiovascular disease(CVD) is the predominant cause of mortality, and AGE accumulationis severely increased in HD patients (16,26). For these reasons,we analyzed the influence of skin AF on overall and cardiovascularmortality in a population of HD patients. Furthermore, we showpreliminary results of the validation of the AFR as a measureof AGE accumulation by comparison with the AGE content in skinbiopsies from HD patients.
Study Population
All 109 patients who were on chronic HD treatment at the DialysisCentre Groningen were observed prospectively, and in 29 of them,skin biopsies were retrieved. Minimum duration of HD was 30d. No further exclusion criteria were used. Patients receivedstandard medical care as appropriate for HD patients. Medicationof patients included antihypertensives (47%), epoetin and irongluconate (21%), aspirin (36%), vitamins (49%), lipid-loweringagents (19%), and phosphate binders (40%). Patients were dialyzedthree times weekly for 4 h with biocompatible low-flux dialyzers(cellulose diacetate and polysulphone). Equilibrated fractionalurea clearance (Kt/V) was aimed at 1.2 per dialysis accordingto Kidney Disease Outcomes Quality Initiative guidelines.
Reference data on normal AFR values were obtained from a groupof 43 nonsmoking, age-matched control subjects. In control subjects,diabetes and renal failure were excluded by conventional criteria(American Diabetes Association) and a serum creatinine <120µmol/L, respectively. HD patients who smoked were notexcluded for the analysis of risk factors related to mortality.
Patient and control characteristics are given in Table 1. Allpatients and control subjects gave informed consent, accordingtot the rules of the local ethics committee.
Table 1. Characteristics of HD patients and control subjectsa
Baseline
An independent physician, who was unaware of AFR results, determinedbefore the beginning of the study whether a patient had CVD.A patient was considered to have CVD when coronary heart disease,peripheral vascular disease, or cerebrovascular disease waspresent (International Classification of Diseases, Ninth Revision,Clinical Modification codes I20, I21, I63, I70, and I73). Hypertensionwas defined as a predialysis systolic BP of >140 mmHg ora diastolic pressure >90 mmHg on at least three occasionsor when receiving antihypertensive medication. Diabetes wasdefined by conventional American Diabetes Association criteria.Duration of renal failure was defined from the date that serumcreatinine was >120 µmol/L to the start of the study.Dialysis duration was defined from the initiation of long-termHD treatment to the start of the study. European Dialysis andTransplant Association classification was used to define theprimary diagnosis of renal failure (27). Primary diagnosis classificationwas simplified into four groups: A, Diabetes, B, hypertension/renovasculardisease, C, primary glomerular disorders, and D, other primarydiagnosis. Laboratory information was collected prospectively.
Follow-Up
Date and cause of death were obtained from medical records aftera follow-up period of 3 yr. Causes of death were certified andclassified as cardiovascular mortality (myocardial infarction,sudden death and stroke, and congestive heart failure) or noncardiovasculardeath (neoplasm, infection, and unknown) according to usualInternational Classification of Diseases coding criteria.
Skin AF
Skin AF was assessed by the AFR (patent PCT/NL99/00607; prototypeof current AGE Reader I; DiagnOptics BV, Groningen, The Netherlands)as described in detail previously (23). In short, the AFR illuminatesa skin surface of approximately 1 cm2, guarded against surroundinglight, with an excitation light source between 300 to 420 nm(peak excitation approximately 350 nm). Only light from theskin is measured with a spectrometer (Ocean Optics PC-1000 fiberoptic spectrometer; Ocean Optics, Dunedin, FL) in the 300- to600-nm range, using 200-µm glass fiber (Farnell, Leeds,UK). The measure of AF that we applied was the average lightintensity per nanometer in the range between 420 and 600 nmdivided by the average light intensity per nanometer in therange between 300 and 420 nm (AF in arbitrary units [AU]).
All measurements were performed at room temperature in a semidarkenvironment before dialysis. Repeated AFR measurements on 1d and intraindividual seasonal variance showed an Altman errorpercentage of <6%. Pre- and postdialysis measured AF didnot differ significantly.
Skin Biopsies
Autofluorescence measurements were followed by full-thicknesspunch skin biopsies (4 mm), taken from the volar side of thelower arm (same location as AFR measurement) under 2% lidocainelocal anesthesia in 29 HD patients. Skin samples were frozenin liquid nitrogen and subsequently stored at –80°C.Skin biopsies were analyzed in a single batch for collagen-linkedfluorescence (excitation at 370 nm, emission at 440 nm) afterpepsin digestion and for pentosidine (by HPLC), CML, and CEL(by gas chromatography–mass spectrometry) content as describedpreviously (23,28).
Statistical Analyses
Comparison between groups was performed with t test or Mann-WhitneyU test for nonnormally distributed variables, and correlationswere analyzed with Spearman rank method. Multivariate regressionanalyses were performed for determination of independent relationshipsof variables with AF. The independent effects of variables onthe presence of CVD at baseline were assessed by logistic regressionanalysis. The cumulative incidence of death during follow-upwas estimated by the Kaplan-Meier method, and the independenteffects and odds ratio (OR) of variables on mortality were estimatedwith stepwise Cox regression model. The primary analysis ofsurvival included all patients, and data were censored at thetime of kidney transplantation. SPSS statistical software (version11.0; SPSS, Inc., Chicago, IL) was used for the analysis; two-tailedP < 0.05 was considered significant. Data are shown as mean(± SD), unless otherwise indicated.
Baseline Table 1 describes baseline characteristics of the HD patientsand control subjects. The median duration of renal failure was4.7 yr (range 9 to 300 mo), and duration on dialysis treatmentwas 2.3 yr (range 1 to 96 mo). Weekly dialysis time was 10.0± 1.9 h.
Figure 1 shows the AF spectrum of the study populations. SkinAF was 2.4 times increased in HD patients compared with controlsubjects (0.024 ± 0.007 versus 0.010 ± 0.001 AU;P < 0.001). AF was increased even further in the subgroupof HD patients with diabetes (n = 23; 0.029 ± 0.002 AU).Sixty-five percent of the variance in AF in HD patients couldbe explained by the independent effects of age (P < 0.001),dialysis (P < 0.001) and renal failure duration (P < 0.001),diabetes (P = 0.001), triglycerides (P = 0.03), and C-reactiveprotein (CRP) levels (P = 0.002). In patients with diabetes,AF correlated with age (r = 0.43, P = 0.04), dialysis duration(r = 0.54, P < 0.01), LDL (r = 0.56, P < 0.01), triglycerides(r = 0.59, P < 0.01), and HbA1c (r = 0.53, P = 0.01). Gender,body mass index, parathyroid hormone levels, and medicationdid not have an independent effect on AF values.
Figure 1. Autofluorescence (AF) spectrum (intensity, arbitrary units [AU]) measured with the AF reader (AFR) in a control subject, a hemodialysis (HD) patient without diabetes, and an HD patient with diabetes; comparable in age, duration of renal failure, and dialysis duration.
Table 2 describes the baseline patient characteristics of thevalidation substudy. AF correlated strongly with collagen-linkedfluorescence (CLF; r = 0.71, P < 0.001) and with pentosidineskin levels (r = 0.75, P < 0.001), as shown in Figure 2.Skin biopsy levels of CLF correlated with pentosidine (r = 0.72,P < 0.01). Furthermore, AF correlated with the nonfluorescentAGE CML and CEL (both r = 0.45, P < 0.01).
Figure 2. The relationship between noninvasive measurement of skin AF (in AU) and skin collagen-linked fluorescence (CLF; AU/µg hyp), and pentosidine (pmol/µg hyp) levels of skin biopsies from 29 HD patients. Hyp, hydroxyproline content of collagen.
Forty-eight HD patients had CVD at baseline, 40 (83%) of whomhad coronary heart disease. Table 3 shows the variables relatedto CVD at baseline. AF was independently related to the presenceof CVD at baseline, as were serum albumin level and CRP.
Table 3. Variables related to the presence of CVD in HD patients at baseline by logistic regression analysisa
Follow-Up
During the follow-up period of 3 yr, 42 (38.5%) patients haddied, which indicates an annual mortality rate of approximately15%. Fifty-five percent of these patients died of CVD. Sevenpatients received a kidney transplant during the follow-up period.
Overall and cardiovascular mortality were markedly increasedin patients with AF values above the group mean AF comparedwith those with values below the group mean AF at baseline (60versus 18%, and 48 versus 8%, respectively; P < 0.001; Figure 3).Patients with CVD at baseline but with AF values below groupmean died predominantly within the first year. Although theirAF values were below group mean, these patients had high AFvalues (0.022 ± 0.001).
Figure 3. Kaplan-Meier estimates of survival during follow-up with regard to overall mortality in HD patients in relation to skin AF above and below mean values, and the presence (±) of cardiovascular disease (CVD) at baseline.
Table 4 shows that AF (OR 3.9), pre-existing CVD (OR 3.1), andalbumin (OR 0.3) were independent predictors of overall mortality.AF was a stronger predictor for cardiovascular mortality (OR6.8; 95% CI 2.6 to 17.5) compared with overall mortality. CRPshowed a borderline significance as predictor of mortality.AF replaced age, diabetes, duration of renal failure, triglycerides,LDL, and parathyroid hormone levels as independent predictorsof mortality. The area under the curve for a receiver operatingcharacteristic curve using AF to detect overall mortality was0.89, and this was higher compared with other measures of metabolicstress (e.g., HbA1c, triglycerides).
Skin AF is a strong and independent predictor of overall andcardiovascular mortality and is associated with CVD in HD patients.Our data indicate that increased skin AF reflects increasedAGE accumulation (CLF and pentosidine). Thus, this study isthe first to show the predictive value of tissue AGE (pentosidine)accumulation for mortality. Our results confirm the clinicalcorrelates of CVD with recognized risk factors, such as diabetesand albumin levels (26,29,30). The noninvasive AFR may becomea clinical desktop tool for risk assessment in ESRD.
The power of skin AF as a prognostic factor for mortality isillustrated by the fact that it was found to serve better inthe Cox regression models than the prognostic value of otherknown risk factors. In this and previous studies, skin AF wasrelated to metabolic stress (HbA1c and hyperlipidemia) and theaccumulation of pentosidine, CML, and CEL (21,23). We hypothesizethat by representing the existing tissue damage from cumulativemetabolic stress, skin AF and AGE accumulation may show theeffect of a common pathway more than traditional risk factorsalone. AGE accumulate as a result of nonenzymatic glycation,oxidative/carbonyl stress, and/or diminished clearance of AGEprecursors (3,4,31). Hyperlipidemia may contribute in the tissueaccumulation of advanced lipoxidation end products (ALE), whichmay contribute to tissue and skin AF (32). Indeed, in our study,skin AF correlated strongly with triglycerides and LDL levels.The quantitative relationship between AGE and ALE in diabetesand ESRD is still unknown, but dyslipidemia may be as importantas hyperglycemia in chemical modification of proteins (32).
Tissue AGE accumulation was also independently associated withthe presence of CVD at baseline in our study. In ESRD, AGE/ALEaccumulate in the vessel wall and contribute to the progressionof CVD by several mechanisms, including cross-linking of extracellularproteins (e.g., LDL), binding to receptor for AGE inducing oxidativestress, inflammation, and endothelial dysfunction (5,8,9,33).Indeed, we observed a strong correlation between skin autofluorescenceand CRP. Altogether, this may accelerate coronary atherosclerosisand induce cardiac remodeling and ventricular dysfunction (34,35).Intervention studies with an AGE breaker have demonstrated improvedvascular and ventricular compliance (13).
A limitation of our study is that we cannot exclude completelythe influence of other uremic toxins or skin fluorophores onskin AF measurements. Furthermore, the current understandingof physiologic AGE indicates that most AGE are not fluorescent.Importantly, fluorescence represents group reactivity, whichfails to provide quantitative information on concentrationsof individual compounds. However, our previous results in patientswith diabetes and these results in HD patients show that skinAF may function as a marker of the AGE pool, on the basis ofthe strong correlations with both fluorescence and nonfluorescentskin AGE levels (23). This study was neither of sufficient sizenor intended to define further the relationship and kineticsof skin AF with tissue and serum AGE accumulation in relationto specific modalities of renal replacement therapies. A largervalidation study is now in progress, including data of skinAF and skin/serum AGE accumulation in the follow-up after kidneytransplantation.
Schwedler et al. (36) and Busch et al. (37) reported that circulatingAGE do not predict mortality in HD patients. However, serumAGE may be influenced by dialysis modalities, absorption fromfood, and smoking (38–40). High serum AGE might even reflecta better nutritional support, associated with improved survival(36). An alternative explanation is that serum AGE may not adequatelyreflect tissue AGE accumulation (21).
Because long-term complications and skin AF are time-dependentprocesses, the results of our study could be biased by age.To reduce such a bias, we always included age as a variablein the multivariate analysis. Furthermore, our study shows acorrelation between skin AF and mortality. Whether this concernsa causal relationship has to be decided by interventions aimedat reducing AGE accumulation.
In conclusion, our study shows that skin AF is an independentpredictor of mortality and is associated with CVD in HD patients.As AF was related to AGE accumulation, our study supports theimportant clinical impact of AGE accumulation in the pathogenesisof vascular disease and is the first to show the prognosticpower of AGE accumulation in renal failure. A growing body ofevidence on the role of AGE in chronic age-related diseaseswarrants interventions that specifically are aimed at AGE accumulation.The noninvasive AFR may become a rapid clinical desktop toolfor risk assessment but also provides a novel approach for monitoringthe role of AGE in disease.
Acknowledgments
This work was supported by a grant from the National Instituteof Diabetes and Digestive and Kidney Diseases (DK-19971) andfrom the Diabetes Fonds Nederland (DFN 2000.00.006).
Footnotes
Conflict of interest: R.G. and A.J.S. both are founders of DiagnOpticsBV, which manufactures autofluorescence readers. This studywas not financially supported by DiagnOptics BV, and final approvalwas always by the first author (R.M.), who is not a member ofDiagnOptics.
Published online ahead of print. Publication date availableat www.jasn.org.
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R. Meerwaldt, H. L. Lutgers, T. P. Links, R. Graaff, J. W. Baynes, R. O.B. Gans, and A. J. Smit Skin Autofluorescence Is a Strong Predictor of Cardiac Mortality in Diabetes
Diabetes Care,
January 1, 2007;
30(1):
107 - 112.
[Abstract][Full Text][PDF]
H. Koyama, T. Shoji, S. Fukumoto, K. Shinohara, T. Shoji, M. Emoto, K. Mori, H. Tahara, E. Ishimura, R. Kakiya, et al. Low Circulating Endogenous Secretory Receptor for AGEs Predicts Cardiovascular Mortality in Patients With End-Stage Renal Disease
Arterioscler. Thromb. Vasc. Biol.,
January 1, 2007;
27(1):
147 - 153.
[Abstract][Full Text][PDF]
H. L. Lutgers, R. Graaff, T. P. Links, L. J. Ubink-Veltmaat, H. J. Bilo, R. O. Gans, and A. J. Smit Skin Autofluorescence as a Noninvasive Marker of Vascular Damage in Patients With Type 2 Diabetes
Diabetes Care,
December 1, 2006;
29(12):
2654 - 2659.
[Abstract][Full Text][PDF]
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Abstract
Introduction
