N {epsilon}-(carboxymethyl)lysine, N {epsilon}-(carboxyethyl)lysine and vascular cell adhesion molecule-1 (VCAM-1) in relation to peritoneal glucose prescription and residual renal function; a study in peritoneal dialysis patients

Jos van de Kerkhof3, Casper G. Schalkwijk2, Constantijn J. Konings3, Emile C. Cheriex1, Frank M. van der Sande1, Peter G. Scheffer2, Piet M. ter Wee2, Karel M. Leunissen1 and Jeroen P. Kooman1

1University Hospital Maastricht, 2Vrije Universiteit Medical Centre, Amsterdam and 3Catharina Hospital, Eindhoven, The Netherlands

Correspondence and offprint requests to: Jeroen P. Kooman, MD PhD, Department of Internal Medicine, University Hospital Maastricht, PO Box 5800, 6202 AZ Maastricht, The Netherlands. Email: jkoo{at}groupwise.azm.nl



   Abstract
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Advanced glycation end products (AGEs) may contribute to peritoneal and cardiovascular damage in peritoneal dialysis (PD) patients, possibly in part by over-expression of vascular cell adhesion molecule-1 (VCAM-1). It has been suggested that peritoneal glucose load, oxidative stress, as well as the uraemic state itself may lead to an increased formation of AGEs. Aims of the present study were first to investigate the relation between residual glomerular filtration rate (rGFR), malondialdehyde (MDA) as a marker of lipid peroxidation, and peritoneal glucose prescription and absorption with serum levels of VCAM-1 and with the well characterized AGEs N{epsilon}-(carboxymethyl)lysine (CML) and N{epsilon}-(carboxyethyl)lysine (CEL), as well as with CML and CEL in peritoneal effluent.

Methods. CML and CEL were measured by tandem mass spectroscopy, MDA by HPLC, and VCAM-1 by ELISA in 37 stable PD patients (age 54 ± 12 years; time on PD 25 ± 18 months). CML and CEL were also measured after a 4-month interval.

Results. rGFR was independently related to CML both in serum (r = –0.66; P<0.001) and effluent (r = –0.62; P<0.001), whereas peritoneal glucose prescription and absorption were, respectively, related to CML in serum and effluent (r = 0.49; P<0.001 and r = 0.44; P<0.01). Relationships were comparable when assessed after the follow-up period. Peritoneal glucose absorption (r = 0.37; P<0.05), but not rGFR, was related to CEL in serum. The relation between peritoneal glucose prescription and CML in effluent lost significance when rGFR was added to the multi-regression model. Both rGFR (r = –0.40; P<0.05) and peritoneal glucose absorption (r = 0.37; P<0.05) were associated with VCAM-1 expression, which was itself weakly related only to CML in effluent (r = 0.38; P<0.05). MDA was not related to any parameter.

Conclusion. Peritoneal glucose prescription and absorption, as well as rGFR are related to serum and effluent levels of CML and to VCAM-1 expression in serum, whereas peritoneal glucose absorption was related to serum levels of CEL. Still, the effect of rGFR, which does not appear to be mediated through lipid peroxidation pathways, on effluent levels of CML appears to outweigh the effect of the PD treatment. Even small differences in residual renal function in patients already on dialysis therapy are related to large variations of CML in serum and the peritoneal cavity.

Keywords: advanced glycation end products; N{epsilon}-(carboxyethyl)lysine; N{epsilon}-(carboxymethyl)lysine; peritoneal dialysis; vascular cell adhesion molecule-1



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Advanced glycation end products (AGEs) accumulate in chronic renal failure. AGEs are formed by the reaction of reducing sugars with amino groups in proteins through a series of oxidative and non-oxidative reactions [1]. The pathophysiologic consequences of the accumulation of AGEs in uraemia is not entirely clear, which is partly due to the heterogeneity of AGE compounds and technical difficulties in their determination [2]. Nevertheless, they are assumed to contribute to a variety of complications such as dialysis-related amyloidosis, vascular wall abnormalities and damage of the peritoneal membrane in peritoneal dialysis (PD) patients [1]. Both a reduced removal and increased generation may contribute to the accumulation of AGEs in patients with end-stage renal disease (ESRD). In patients with normal kidney function, AGE modified proteins are removed by the kidney after degradation by specific AGE receptors. Apart from a reduced removal by the loss of kidney function, the generation of AGEs may be enhanced by the stimulation of auto-oxidation pathways in patients with ESRD [1]. In PD patients, AGE formation may be further stimulated by accumulation of reactive carbonyl intermediates, also called glucose degradation products (GDP). These were shown to be present in conventional PD fluid due to degradation of glucose by the sterilization process [1,3]. Moreover, GDP's present in peritoneal dialysate may be transported from the peritoneal cavity into the blood, leading to increased plasma levels of AGE compounds [4].

One of the best characterized AGEs is N{epsilon}-(carboxymethyl)lysine (CML), which has been identified as the major non-fluorescent AGE in uraemia [5]. The formation of CML may be mediated through GDP such as glyoxal and 3-deoxyglucosone [57], but also from oxidative non-enzymatic (metal chelated) changes to Schiff base or Amadori products [6,8]. In addition to glycoxidation pathways, lipid peroxidation was also shown to contribute to CML formation [5,7,8]. Thus, CML is not a specific biomarker, derived from a single precursor [7].

Moreover, although it is clear that both the uraemic state and the PD treatment itself may lead to accumulation of CML in plasma and peritoneal effluent, the relative importance of both variables has not yet been elucidated.

Another well characterized AGE compound is N{epsilon}-(carboxyethyl)lysine (CEL), which is mainly formed by a non-enzymatic reaction between methylglyoxal and lysine. The importance of other intermediate compounds in the formation of CEL is less clear [7]. Thus, the pathways contributing to CEL formation appear to be more limited compared with CML [7].

CML has been implicated in the pathophysiology of various dialysis-related complications such as amyloidosis, vascular wall abnormalities and damage of the peritoneal membrane [1,6]. Part of the potential deleterious effect of CML on the vascular wall is supposed to ensue from the activation of endothelial cells indicated by the induction of adhesion molecules such as vascular cell adhesion molecule-1 (VCAM-1). CML increased VCAM-1 expression on endothelial and mesothelial cells after ligation to the receptor for AGE (RAGE) [9]. The possible pathophysiologic role of CEL has been studied less well compared with CML. However, CEL was also shown to accumulate in tissue proteins [7].

The aim of the present study was first to assess the relative importance of residual renal function, lipid peroxidation and peritoneal glucose load on serum and effluent levels of CML and CEL. Secondly, we studied the relation between CML and CEL with soluble (s)VCAM-1 expression in serum.



   Subjects and methods
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 Subjects and methods
 Results
 Discussion
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Study design
The relation between residual renal function and peritoneal glucose absorption with serum and effluent levels of CML and CEL was studied in a cross-sectional design. Also, the relation of these parameters with VCAM-1 expression in serum was assessed. Serum and effluent levels of CML, and serum levels of CEL were also measured after a follow-up period of 4 months, during which treatment prescription was not changed.

Eligible patients, whom did not meet the exclusion criteria, were asked to participate in the study. Exclusion criteria were: acute intercurrent infection, malignancy, cardiac failure (NYHA>II) and diabetes mellitus, and use of non-glucose peritoneal solutions. All patients were treated only with standard glucose containing lactate-buffered peritoneal solutions (Dianeal®; Baxter, Castlebar, Ireland). Thirty-two patients were treated with continuous ambulatory PD, whereas five patients were treated with continuous cyclic PD. The glucose concentration was prescribed at the discretion of the treating physician. CML and CEL in dialysate were assessed in a sample taken from the entire 24-h dialysate collection.

The study was approved by the Ethical Committee of the University Hospital Maastricht.

Patients
Thirty-seven patients on PD were included. The baseline characteristics of these patients are given in Table 1. The causes of renal insufficiency were: glomerulonephritis, 19 patients; glomerulosclerosis, four patients; hypertension, six patients; polycystic disease, four patients; urological disorder, three patients; scleroderma, one patient. For 25 patients, follow-up data for CML and CEL are available. Reasons for drop-out were: renal transplantation (n = 4), peritonitis (n = 2), switch to haemodialysis because of technique failure (n = 2), refusal of second measurement (n = 3) and termination of PD treatment because of return of renal function (n = 1).


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Table 1. Patient demographics and study parameters

 
Study parameters
Peritoneal glucose prescription and absorption. The transport characteristics of the peritoneal membrane (D/P = dialysate-to-plasma creatinine ratio) were characterized using a standard peritoneal equilibrium test after a 4-h dwell with a 2.27% glucose solution. The day before the investigation, 24 h collection of the peritoneal effluent and the urine was performed. The 24 h peritoneal glucose dosage prescription was calculated from the volume and glucose concentration of the prescribed PD fluid. Peritoneal glucose absorption was calculated as the difference between peritoneal glucose prescription and the amount of glucose in the peritoneal effluent. Residual renal function was assessed by estimation of the residual glomerular filtration rate (rGFR), which was expressed as the mean of the urea and creatinine clearance obtained from the 24-h urine collection.

Moreover, normalized protein catabolic rate (nPCR), as well as adequacy of dialysis, expressed by Kt/V and creatinine clearance were assessed from the 24-h peritoneal effluent and urine collection, and calculated by the PD adequest program (Baxter Healthcare; Round Lake; Illinois; USA®).

Laboratory parameters. Detection of CML and CEL by LC/MS/MS: to 25 µl of serum, 500 µl 100 mmol/l sodium borohydride was added. After 4 h at room temperature trichloroacetic acid was added and precipitated proteins were pelleted by centrifugation. After addition of d4-CML and d8-CEL as internal standards (kindly provided by Drs J. Baynes and S. Thorpe), proteins were hydrolysed overnight with 6 mol/l HCl and after evaporation of HCl under nitrogen the residue was dissolved in 5 mM nonafluoropentanoic acid (NFPA). CML and CEL were resolved by reversed-phase high performance liquid chromatography (HPLC) using NFPA as ion-pair reagent. All analyses were performed on an API 3000 triple quadruple mass spectrometer (PE Sciex) operating in the positive-ion mode. The transition of protonated CML and CEL to fragment m/z 84 was used for MRM analyses. Within-day and between-day CVs were <4.4 and <3.2% for CML and <6.8 and <7.3% for CEL. The concentrations of CML and CEL are expressed per amount of lysine. Dialysate levels of CEL were beyond the detection limit of the assay. sVCAM-1 was assayed by Elisa (Diaclone, Besancon, France) with intra- and inter-assay coefficients of variation of 4.0 and 8.6%, respectively. The mean values for VCAM-1 obtained in 200 healthy controls was 1019 ng/ml (95% confidence interval 889–1155).

Malondialdehyde (MDA) was assessed by a modified method based on the approach of Hong et al. [10]. The level of MDA in serum was determined after reaction with thiobarbituric acid (TBA) with an added alkaline hydrolysis step [1]. In brief, to 50 µl of serum 25 µl of 0.2% BHT and 400 µl 1 N NaOH was added. The mixture was incubated at 60°C for 60 min in a shaking water bath. After cooling to room temperature 1.5 ml of 10% TCA containing 1% KI was added, and the mixture was placed in ice for 10 min and centrifuged at 1500 g for 10 min at 4°C. To 0.5 ml of the supernatant 0.25 ml 0.6% TBA was added, and the mixture was heated at 95°C for 30 min. After centrifugation (1500 g, 10 min) 50 µl of the supernatant was injected into a symmetry C-18 column (Waters 4.6 x 100 mm, 3.5 µm) eluted at 1 ml/min by using 70% (v/v) 25 mmol/l KH2PO4 (pH 6.8) and 30% (v/v) methanol. Detection of the MDA–TBA adduct was performed with fluorescence detection (excitation at 515 nm and emission at 553 nm). For quantification intensities of the MDA–TBA peaks were compared with a standard curve constructed with tetraethoxypropane (Sigma). The between run variation was 3.5%.

Moreover, in all PD patients, blood samples were also taken for the assessment of albumin and C-reactive protein (CRP) (Syncron LX 20, Beckman Coulter, CA, USA). The detection limit of the CRP assay was a value of 2 mg/ml.

Statistical analysis
Correlations between the different parameters were estimated by the use of Pearson product moment correlations. Stepwise linear multi-regression analysis was used where appropriate.

Calculations were made using SPSS 11.1 statistical software for Windows. P-values <0.05 were considered significant. Data are expressed as mean ± SD.



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Determination of CML and CEL, and VCAM-1 levels failed in two patients. rGFR was related to CML both in serum (r = –0.62; P<0.001) (Figure 1) and peritoneal effluent (r = –0.69; P<0.001) (Figure 2). CML in serum and dialysate were highly significantly related (r = 0.81; P<0.001). Peritoneal glucose prescription was related to CML in peritoneal effluent (r = 0.44; P<0.001) whereas peritoneal glucose absorption was related to CML in serum (r = 0.49; P<0.001) (Figure 3). Multivariate analysis showed that rGFR and peritoneal glucose absorption were both independent predictors of CML in serum (t = –4.3; P<0.001 and t = 2.5; P<0.05, respectively; r2 of model = 0.52; P<0.001). In contrast, peritoneal glucose prescription lost significance as a predictor for CML in peritoneal effluent, when rGFR was added to the multi-regression model (t = 1.3; P = ns and t = –4.3; P<0.001, respectively; r2 of model = 0.50; P<0.001). Also, CML levels in serum and effluent, measured after the follow-up period of 4 months, were significantly related to, respectively, peritoneal glucose absorption (r = 0.43; P<0.05) and load (r = 0.43; P<0.05) at baseline. Also, the relation between rGFR and serum and effluent levels of CML, when repeated after 4 months, remained significant (r = –0.62; P<0.001 and r = –0.56; P<0.01, respectively).



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Fig. 1. Relation between rGFR and CML levels in serum. rGFR, residual glomerular filtration rate; CML, N{epsilon}-(carboxymethyl)lysine (µmol/mmol Lys). r = –0.62; P<0.001.

 


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Fig. 2. Relation between rGFR and CML levels in peritoneal effluent. rGFR, residual glomerular filtration rate; CML, N{epsilon}-(carboxymethyl)lysine (µmol/mmol Lys). r = –0.69; P<0.001.

 


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Fig. 3. Relation between peritoneal glucose absorption and CML levels in serum. CML, N{epsilon}-(carboxymethyl)lysine (µmol/mmol Lys). r = 0.49; P<0.001.

 
CEL in serum at baseline (r = 0.37; P<0.05) and after 4 months (r = 0.46; P<0.05) was weakly related to peritoneal glucose absorption (r = 0.37; P<0.05), but not to rGFR. The concentration of CEL in peritoneal effluent was below the detection limit of the assay. Serum levels of CML and CEL were related (r = 0.66; P<0.001).

Both rGFR (r = –0.40; P<0.05) and peritoneal glucose absorption (r = 0.37; P<0.05) were associated with sVCAM-1 expression in serum (Figure 4), although the multi-regression model was to weak to elucidate the relative importance of both factors (t = –1.7; P = 0.09 and t = 1.7; P = 0.09, respectively; r2 of model = 0.21; P<0.05).



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Fig. 4. Relation between rGFR and VCAM-1 expression in serum. rGFR, residual glomerular filtration rate. r = –0.40; P<0.05.

 
sVCAM-1 expression in serum was weakly related only to CML in peritoneal effluent (r = 0.38; P<0.05) but not to CML in serum. MDA was not related to any parameter.

Age, CRP, the D/P creatinine ratio, Kt/V, nPCR, total peritoneal fill volume and time on dialysis treatment were not independently related to either serum or dialysate levels of CML and CEL or VCAM-1 expression.



   Discussion
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
The main findings of the present study were first the significant relation between peritoneal glucose absorption with serum levels of CML and CEL, and especially the strong inverse relation between rGFR with CML in both serum and peritoneal effluent. Secondly, sVCAM-1 expression in serum was weakly related both to peritoneal glucose absorption and to rGFR, as well as to CML levels in peritoneal effluent.

The relationship between peritoneal glucose absorption and serum levels of CML and CEL can be explained either by transport of GDP from the dialysate into the systemic circulation, as has been suggested by Zeier et al. [4], or by direct transport of AGEs from the dialysate into the systemic circulation. It has been shown that GDP such as glyoxal and 3-deoxyglucosone are important precursors in the formation of CML [5] and methylglyoxal in the formation of CEL. Although the absorption of GDP from the peritoneal cavity into the blood is a matter of debate, absorption of GDP from the peritoneal cavity into the blood could explain the relation between peritoneal glucose absorption of serum levels of CML and CEL. The observed relationships were, however, not very strong, which may be explained partly by the fact that i.p. inflammation, which was not assessed in the present study, can have a major influence on the glucose absorption from peritoneal cavity to plasma [11].

The relation of peritoneal glucose prescription with CML levels in peritoneal effluent may be explained by the presence of reactive carbonyl compounds, which are present in large concentrations in the conventional glucose-based dialysis fluids used in the present study [3]. In an earlier study, CML formation in peritoneal effluent appeared to be related to peritoneal glucose concentration [12].

In this study we demonstrated that in patients already on dialysis therapy, CML levels in serum were strongly and inversely related to rGFR. The observation of the present study is in agreement with earlier observations regarding an inverse relation between pentosidine and residual diuresis in patients with ESRD [13]. The inverse relation between renal function and CML has also been reported previously, but only in patients with diabetes mellitus type II and mild renal disease [14].

The inverse relation between rGFR and serum levels of CML might be explained by either a reduced excretion through the kidney or by an increased formation by pro-oxidant stress or inflammation, which are known contributing factors to the formation of CML [5,6]. The fact that the majority of CML in plasma is albumin bound [1] makes it less likely that a reduced rGFR is the sole explanation for the observed relationship. Markers of oxidative stress and inflammation increase along the course of renal failure [15,16]. As MDA was not related to CML levels, there appears to be no strong argument for lipid peroxidation as the explanatory factor for the observed relations between rGFR and CML levels. With regard to inflammation, a potentially relevant, but not yet widely studied factor in the pathogenesis of CML formation is myeloperoxidase activity, which is increased in renal failure [17].

rGFR was also independently related to CML in the peritoneal effluent, which confirms earlier observations that the uraemic state itself plays an important role in peritoneal AGE expression [18]. Indeed, the results of the present study suggest that the effect of rGFR may even outweigh the effect of the dialysis treatment on CML formation in the peritoneal cavity. Interestingly, serum levels of CEL were not related to rGFR, but only weakly to peritoneal glucose absorption. This might be explained by the fact that pathways leading to CEL formation are more limited compared to those leading to formation of CML. As discussed previously, the formation of CML is stimulated by a variety of oxidative and inflammatory pathways, whereas the formation of CEL is mainly based on the reaction between methylglyoxal and lysine [3,5].

AGEs have been implicated in the pathogenesis of accelerated atherosclerosis in uraemic patients [4]. CML might contribute to vascular wall damage by increased expression of VCAM-1 [9], which is an important member of a supergene family of adhesion molecules [19] on endothelial and mesothelial cells. VCAM-1 expression is stimulated through activation of RAGE, whereas CML is a ligand with a very strong affinity for RAGE [9].

However, only a weak relation between sVCAM-1 expression and CML levels in peritoneal effluent, but not in serum, was observed in the present study. sVCAM-1 expression was also weakly related to both peritoneal glucose absorption and rGFR. Due to the weak relationships, it was not possible to assess the relative importance of both factors on VCAM-1 expression by multivariate analysis. The relation between VCAM-1 expression and renal function is in agreement with earlier studies in patients with less severe renal disease [20]. Due to the high molecular weight (90–110 kDa) of VCAM-1, it appears unlikely that a reduced removal by the kidney would be the sole explanation for the inverse relation between rGFR and VCAM-1 expression. Although CRP levels were not related to VCAM-1 expression in the present study, the role of inflammation in the enhancement of VCAM-1 expression in uraemic patients needs to be further elucidated by the use of more detailed markers.

In view of the fact that AGE formation is a chronic process, an obvious drawback of the present study is the fact that relations were partly studied in a cross-sectional design, although with regard to serum and effluent levels of AGEs, also longitudinal data are included. Although the follow-up time would appear somewhat short, an earlier study showed clear differences in serum levels of CML after a change in PD solutions after a treatment period of 8 weeks [4]. Moreover, the relatively modest number of included patients hampers especially the interpretation of the weaker relationships. Moreover, the pathophysiologic background behind our observations needs to be studied in more detail. Especially the role of inflammation deserves further consideration.

Concluding, the present study showed that both peritoneal glucose prescription and absorption, as well as rGFR were found to be related to CML in serum and peritoneal effluent, and to VCAM-1 expression in serum, whereas peritoneal glucose absorption was weakly related to serum levels of CEL. Still, the effect of rGFR on CML levels in peritoneal effluent appears to outweigh the effect of the PD treatment. Thus, even small differences in renal function in patients already on dialysis therapy are related to large variations of CML in the blood and peritoneal cavity.

Conflict of interest statement. None declared.



   References
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 29. 4.03
Accepted in revised form: 29.10.03