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NDT Advance Access originally published online on March 8, 2007
Nephrology Dialysis Transplantation 2007 22(7):2020-2026; doi:10.1093/ndt/gfm050
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© The Author [2007]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Receptor for advanced glycation end products—soluble form and gene polymorphisms in chronic haemodialysis patients

Marta Kalousová1, Marie Jáchymová1, Oto Mestek4, Magdaléna Hodková2,3, Markéta Kazderová2, Vladimír Tesar2 and Tomás Zima1

1Institute of Clinical Chemistry and Laboratory Diagnostics, 2Department of Nephrology, 3Department of Medicine Strahov, First Faculty of Medicine and General University Hospital, Charles University and 4Institute of Chemical Technology, Prague, Czech Republic

Correspondence and offprint requests to: Marta Kalousová, Institute of Clinical Chemistry and Laboratory Diagnostics, 1st Faculty of Medicine and General University Hospital, Charles University, Karlovo nám. 32, 121 11 Prague 2, Czech Republic. Email: marta.kalousova{at}seznam.cz, mkalousova{at}hotmail.com



   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Results
 Discussion
 Acknowledgements
 References
 
Background. The receptor for advanced glycation end products (RAGE) is involved in the pathogenesis of vascular and inflammatory diseases. The pathological effects mediated via RAGE are physiologically inhibited by soluble RAGE (sRAGE). Our aim was to study sRAGE and RAGE gene polymorphisms in haemodialysis (HD) patients.

Methods. A total of 261 stable HD patients were enrolled in the study and prospectively followed up for 30 months. At the begining of the study, sRAGE inflammatory and nutritional parameters were determined. RAGE polymorphisms were determined in a subgroup of 214 HD patients. A group of 100 healthy controls was used for comparison.

Results. In HD patients, sRAGE is elevated in comparison with healthy controls (3427 ± 1508 vs 1758 ± 637 pg/ml, P < 0.001). It correlates negatively with residual diuresis (r = –0.193, P < 0.05), with the acute phase reactants fibrinogen (r = –0.174, P < 0.05) and orosomucoid (r = –0.135, P < 0.05) and with the leucocyte count (r = –0.158, P < 0.05). On the other hand, it is not related to the presence of diabetes mellitus, cardiovascular disease, nutritional status and mortality. The highest sRAGE levels are found in –429 CC and 2184 GG polymorphisms of the RAGE gene. The same results as for sRAGE were obtained for endogenous secretory RAGE (esRAGE), which correlated significantly with sRAGE (r = 0.88, P < 0.001).

Conclusion. We conclude that in HD patients, sRAGE is increased due to decreased renal function, which is a very strong determinant of sRAGE levels, and is inversely related to inflammation. The highest sRAGE levels are influenced genetically. In our study, sRAGE levels were not related to mortality of HD patients.

Keywords: endogenous secretory receptor for advanced glycation end product, esRAGE; haemodialysis; inflammation; RAGE polymorphisms; soluble receptor for advanced glycation end products, esRAGE



   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Results
 Discussion
 Acknowledgements
 References
 
The receptor for advanced glycation end products (RAGE) is involved in the pathogenesis of many diseases and their complications, including inflammatory or vascular diseases or diabetic complications [1,2]. Several studies have focused on the genetic background of RAGE and have demonstrated that some gene polymorphisms are associated with amplification of the inflammatory response [3], with diabetic complications [4,5] or with coronary atherosclerosis [6,7].

Soluble RAGE (sRAGE), or endogenous secretory RAGE (esRAGE), is a naturally occurring inhibitor of pathological effects mediated via RAGE [8,9]. It is a RAGE isoform lacking the C-terminal (transmembrane) domain, and in humans it results from alternative splicing of RAGE mRNA [10]. A decrease of this protective factor was observed in patients with coronary artery disease in the general population [11] as well as in patients with hypertension [12] or diabetes mellitus with complications [13,14]. On the other hand, in patients with decreased renal function, mainly in end-stage renal disease patients (ESRD), sRAGE is increased [15], although these patients are at high cardiovascular risk and often have hypertension or diabetes—factors which decrease sRAGE. Renal function is probably influenced by by sRAGE [15], however, the contribution of the other, yet unknown mechanisms currently cannot be fully excluded.

The study was aimed at investigating the role of sRAGE in haemodialysis (HD) patients, its relationship to comorbidities (diabetes, cardiovascular disease, hypertension), as well as to inflammatory and nutritional parameters, and particularly at the association of sRAGE with selected RAGE gene polymorphisms and at the relationship to mortality of HD patients.



   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Results
 Discussion
 Acknowledgements
 References
 
Study population
A total of 261 unrelated Caucasian patients on chronic HD from six dialysis centres, all of them in stable clinical status, were enrolled in the study. In these patients, basic characteristics like age, sex, gender, body mass index as well as data related to their primary renal diseases, to the dialysis treatment and comorbidities (diabetes mellitus, hypertension, coronary artery disease, treatment, etc.) were collected. In all of these patients, selected biochemical parameters were measured at the beginning of the study. Material for genetic analysis was available from 214 of these patients. All patients were prospectively followed up for 30 months from November 2003 to May 2006. Causes of death were recorded and finely classified by two independent physicians as cardiovascular, infection, tumour and others.

One hundred unrelated Caucasian healthy subjects served as controls, in 89 of whom an additional genetic analysis was performed.

The study was performed in adherence to the principles of the Declaration of Helsinki and approved by the Institutional Ethical Committee (registration numbers 26/03 and 1/04 Elpida). All patients gave their informed consent prior to entering the study (extra informed consent for biochemical and genetic analysis). The study is registered as a clinical trial in The Cochrane Renal Group Registry <http://www.cochrane-renal.org/dbsearch.php> and its identification number is CRG110500022.

Characteristics of haemodialysis patients
The studied group of HD patients consisted of 141 men (54%) and 120 women (46%), mean age 63.5 ± 13.1 years. All patients were in stable clinical status at the beginning of the study. Their primary renal diagnosis was as follows: diabetic nephropathy in 51 cases (19.5%), hypertensive nephropathy in 26 cases (10%), interstitial nephritis in 70 cases (26.8%), glomerulonephritis in 53 cases (20.3%), polycystic kidney disease in 38 cases (14.6%) and multifactorial in 23 cases (8.8%). Their mean residual diuresis was 715 ml/24 h. The majority of the patients were dialysed three times a week for 4 h and their dialysis treatment lasted for 2 years (1–4 years). They received 5620 ± 2406 IU heparin per session, their mean ultrafiltration per session was 714 ml and Kt/V 1.35 ± 0.23. HD treatment was performed using conventional bicarbonate-buffered dialysate in all patients. Of all patients, 89% used native arteriovenous fistulae for dialysis; in other cases, arteriovenous fistula with artificial graft was used. Eighty-nine percent of patients were dialysed with low flux dialysers and, in the rest of the group either high flux dialysers or both high and low flux dialysers were used. Dialyser membranes were made of polysulphone (44.8%), diacetate cellulose (34.5%), triacetate cellulose (7.7%), polymethylmetacrylate (5.7%) and polyamide (7.3%). Table 1 depicts laboratory characteristics of HD patients and their comparison with controls. Residual diuresis in each renal diagnosis is shown in Table 2.


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  		Table 1. Laboratory characteristics of HD patients, comparison with healthy controls

 

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  		Table 2. Residual diuresis and sRAGE in patients with various causes of renal failure

 
Thirty-three percent of patients suffered from diabetes mellitus (half of them were treated with insulin) and 41% had dyslipidaemia (27% were treated with statins and 5% with fibrates). Case history of 84% patients included hypertension, cardiovascular disease was present in 61% (acute myocardial infarction in 16.5%), cerebrovascular diseases in 24% and peripheral vascular disease in 25%. Of all patients, 11% were malnourished and 20% were smokers. Seventy-one percent of patients were presently treated with antihypertensive drugs (angiotensin-converting enzyme inhibitors or angiotensin II receptor 1 blockers in 51%, beta-blockers in 49%, calcium channel blockers in 30% and nitrates in 18% of the total number of patients). Other drugs included diuretics (in 70% of patients), aspirin or other antiplatelet drugs (67% of patients), iron, erythropoietin (a weekly average dose of 75 IU/kg body weight), phosphate binders (predominantly calcium carbonate), and vitamin D, occasionally vitamin B and C supplementation.

Samples
In the HD patients, blood was collected via puncture of the arteriovenous fistula before starting the dialysis session and prior to heparin administration. In the control subjects, blood was collected after overnight fasting via puncture of the cubital vein, simultaneously with blood collection for routine control examinations. Blood count, routine biochemical parameters (in blood without anticoagulant, determination in serum) and fibrinogen (tube with sodium citrate as anticoagulant) were determined in fresh samples. For DNA analysis, blood was collected into tubes containing ethylene diamine tetraacetic acid (ETDA), tubes were stored at –4°C and isolation of DNA was performed within 1 week. For special biochemical analysis, blood was collected into tubes without anticoagulant, centrifuged for 10 min at 3000 rpm (rotations per minute) and serum was frozen at –80°C. Analysis of all samples was performed within 6 months after collection.

Laboratory parameters
RAGE polymorphisms—genotyping
The gene encoding RAGE is located on chromosome 6p21.3 and comprises 11 exons (spanning 3.27 kb). Four polymorphisms of the RAGE gene –429T/C, –374 T/A, Gly82Ser and 2184 A/G were determined from DNA extracted from a sample of peripheral blood. For amplification of the region containing the –374 T/A and –429 T/C polymorphisms, the following primers were used: forward primer 5'GGG GCA GTT CTC TCC TCA CT3' and reverse primer 5'GGT TCA GGC CAG ACT GTT GT3'. Polymerase chain reaction (PCR) amplification was conducted in a 25 µl volume containing 100 ng of genomic DNA and 12.5 pmol of each primer. Annealing temperature was 59.5°C and final extension occurred at 72°C for 7 min. Restriction analysis was performed with all PCR products using three units of restriction nucleases, AluI for –429 T/C and Gly82Ser and MfeI for –374 T/A polymorphisms overnight at 37°C. The restriction products were directly separated by electrophoresis in 3% agarose gel, and visualized in UV-light after ethidium bromide staining. Digestion with MfeI revealed fragments 215 and 35bp for the wild type allele –374 T and 250bp for the mutated allele –374 A. After the digestion reaction with AluI fragments 250bp for –429T allele (wild type) and 88 + 16 2bp for –429C allele were detected. The Gly82Ser polymorphism in exon 3 of the RAGE gene was amplified by PCR using primers 5'GTA AGC GGG GCT CCT GTT GCA3' and 5'GGC CAA GGC TGG GGT TGA AGG3' [16]. The PCR product 397 bp was digested by the AluI enzyme. Genotypes for the Gly82 and Ser82 alleles were detected as bands corresponding to fragment sizes of 248 and 149bp for the wild type allele Gly82, and 181, 67 and 149bp for the minor allele Ser82. We did not identify the restriction site (AluI) in 7128–7131 position of D28769 [GenBank] gen-map [17] by sequencing analysis. Therefore, we have not obtained the bands of lengths 123 and 26 bp, but only the band of 149 bp, in position 7128 T instead A was found. Detection of 2184 A/G polymorphism in intron 8 of the RAGE gene was done according to Kankova et al. 16. The PCR procedure was performed with all samples on two separate occasions.

sRAGE assay
We measured sRAGE with sandwich ELISA (enzyme-linked immunosorbent assay) using standard kits Quantikine, RD Systems, Minneapolis, USA, according to the manufacturer's protocol. In this assay, the plate is coated with a monoclonal antibody against RAGE and a polyclonal antibody is used for detection. Mean minimal detectable dose of RAGE is 4.12 pg/ml. Results are given in pg/ml.

esRAGE assay
We assessed esRAGE with non-competitive ELISA (enzyme-linked immunosorbent assay) using standard kits B-Bridge International, Inc., Mountain View, CA, USA, according to manufacturer's protocol. Results are given in ng/ml.

Other parameters
High-sensitive C-reactive protein (CRP) was determined with turbidimetry on latex particles (Sevafarma a.s., Prague, Czech Republic), orosomucoid (acidic {alpha}1-glycoprotein) was assessed nephelometrically and fibrinogen was measured by the trombin method (Clauss).

Routine biochemical parameters were determined with standard clinical-chemistry methods recommended by the International Federation of Clinical Chemistry (IFCC). Blood count was measured with an automated haematological analyser.

Statistical analysis
The results of biochemical parameters are expressed as mean ± SD, in case of high interindividual variability and non-normal distribution of data as median and interquartile range. The unpaired t-test and Wilcoxon test were used for the evaluation of the differences between groups. Comparison of subgroups was performed with ANOVA and the Kruskal–Wallis test. Associations between parameters were determined using Pearson's and Spearman's correlation coefficients, according to the data distribution.

Concerning the evaluation of RAGE polymorphisms, the significance of differences from Hardy–Weinberg equilibrium as well as those in the genotype distribution and/or allelic frequencies among groups was tested using the {chi}2 test. Haplotype analysis was used for more detailed description.

Survival analysis in the group of HD patients was performed using the Kaplan–Meier method with comparison of curves with log-rank test and Cox's proportional hazard model.

All results were considered as statistically significant at P < 0.05 [18,19].



   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Results
Discussion
 Acknowledgements
 References
 
Clinical and biochemical characteristics of patients according to sRAGE levels, association of sRAGE with selected parameters
Soluble RAGE is elevated in HD patients in comparison with the healthy controls (3427 ± 1508 vs 1758 ± 637 pg/ml, P < 0.001). Patients with diabetic nephropathy as well as patients with renal failure of multifactorial aetiology or polycystic kidney disease have significantly lower sRAGE levels (Table 2). In our study, sRAGE correlated significantly and negatively with residual diuresis (r = –0.193, P < 0.05, Pearson's) and its higher values were observed also in patients with longer duration of the dialysis treatment (mean number of years spent on dialysis in patients with sRAGE above median 3178 pg/ml was 3.87 years, in patients with sRAGE below median 2.38 years, P < 0.05). Also, sRAGE does not depend on the material of the dialysis membrane, but is higher in patients treated with high flux membranes (4374 ± 1407 vs 3362 ± 1498 pg/ml, P < 0.05).

When the HD patients were divided into two groups—one with sRAGE below median and the other with sRAGE above median, there was no difference in the number of men and women in each group, body mass index, smoking, further dialysis characteristics, prevalence of diabetes mellitus, dyslipidaemia, cardiovascular, cerebrovascular or peripheral vascular disease, or medication (neither usage of angiotensin-converting enzyme inhibitors nor angiotensin II receptor 1 blockers). However, incidence of hypertension was higher in the group with higher sRAGE, P < 0.05).

We found that sRAGE correlated significantly and negatively with the acute phase reactants fibrinogen (r = –0.174, P < 0.05, Pearson's) and orosomucoid (r = –0.135, P < 0.05, Pearson's) and with the leucocyte count (r = –0.158, P < 0.05, Pearson's). Also, the relationship to CRP was negative, however, not significant. On the other hand, sRAGE was unrelated to nutritional parameters—albumin, transferrin and cholesterol. Results showed that sRAGE correlates significantly with esRAGE (r = 0.88, P < 0.001, Pearson's and r = 0.95, P < 0.001, Spearman's).

Polymorphisms of the RAGE gene in studied populations
Allelic as well as genotype frequencies of studied polymorphisms of the RAGE gene in HD patients and healthy controls did not differ (Table 3). Genotype frequencies in HD patients and controls did not differ from the Hardy–Weinberg equilibrium. Haplotype analysis did not show differences between the corresponding haplotype frequencies in HD patients and healthy subjects (Table 4).


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  		Table 3. Allelic and genotype frequencies of studied polymorphisms of the RAGE gene in HD patients and healthy controls

 

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  		Table 4. Haplotype frequencies in HD patients and healthy controls (polymorphisms of the RAGE gene: –429 T/C, –374 T/A, Gly82Ser, 2184 A/G)

 
Studying the relationship between RAGE polymorphisms and sRAGE, we have shown that only RAGE –429 T/C (highest levels in CC variant—4837 ± 1358 vs 3180 ± 1571 pg/ml in TC and 3579 ± 1454 pg/ml in TT variant, P < 0.05) and RAGE 2184 A/G (highest levels in GG variant—5204 ± 947 vs 3169 ± 1587 pg/ml in AG and 3571 ± 1444 pg/ml in AA variant, P < 0.05) were associated with sRAGE levels, while the polymorphisms RAGE –374 T/A and Gly82Ser were not. The same results were found for esRAGE. We did not demonstrate any influence of any haplotype either on the sRAGE level or on esRAGE level.

Additionally, no haplotypes were significantly related to the presence of cardiovascular, cerebrovascular or peripheral vascular disease, dyslipidaemia or the presence of diabetes mellitus or hypertension in the case history of HD patients or to their inflammatory state, characterized by basic markers of inflammation (leucocyte count or C-reactive protein).

Relationship of sRAGE and RAGE polymorphisms to mortality
During the follow-up period of 30 months, 101 patients (i.e. 38.6%) died. A total of 48.5% of the deaths were due to cardiovascular causes, while infection was the major cause of deaths in 27.5%, tumours in 10% and other causes in 14% of patients. There was no difference in the sRAGE level in the subgroups of patients divided according to the causes of death. Additionally, the Kaplan–Meier analysis did not demonstrate any difference in patients with sRAGE levels below and above the median, neither in the overall mortality nor in the cardiovascular mortality. Using Cox's proportional hazard model, neither sRAGE, nor esRAGE nor any of the studied RAGE polymorphisms showed a relationship to mortality.



   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
Acknowledgements
 References
 
In this study we demonstrate that soluble RAGE is increased in the HD patients, probably due to a decreased renal function and has an inverse relationship to inflammation. Another important finding is the tight correlation between sRAGE and esRAGE, which allows a unifying view at studies measuring sRAGE and those determining esRAGE although different immunoassays with different antibodies are used.

Renal function is a very strong determinant as shown in our previous study [15], which is further supported by the negative association with residual diuresis in HD patients as well as with the duration of dialysis treatment, since residual renal function continuously diminishes. Additionally, sRAGE positively correlates with AGEs [20–22], which are also related to renal function. However, sRAGE could also be up-regulated to protect against toxic effects exerted by AGEs via RAGE. Other RAGE ligands, particularly EN-RAGE (extracellular newly identified RAGE-binding protein, S100A12 protein/calgranulin), which is present at sites of inflammation [23,24] could also affect sRAGE level. EN-RAGE is increased in diabetic patients [25] as well as in end-stage renal disease patients [26] and was shown to be inversely associated with sRAGE [27]. The inverse relationship of sRAGE to inflammation in HD patients indicates its behaviour (even when at significantly higher levels) is similar to that in the general population, where lower levels in states linked to disease complications, inflammation or microinflammation were found [11–14,28].

In the general population, sRAGE is decreased in diabetes mellitus and even more in its complications [13,14]. Similarly, in the dialysis population, sRAGE is lower in patients with diabetic nephropathy and in renal failure of multifactorial aetiology (diabetic nephropathy + interstitial nephritis and/or hypertensive nephropathy). However, the interpretation of sRAGE in the subgroup of multifactorial aetiology is difficult. The presence of diabetes mellitus had no impact on sRAGE levels, which supports the idea of the strong effect of decreased renal function. Concerning lower levels of sRAGE in polycystic kidney disease, we could speculate there would be better residual renal function in these patients; however, residual diuresis was not higher. The question arises whether in these patients filtered sRAGE may accumulate in the cysts or may be degraded in proximal tubulus cells. The explanation would require further investigation. On the contrary, the presence of hypertension was higher and the group of patients with higher sRAGE levels, probably as a consequence of hypervolaemia in anuric patients, and patients with hypertensive nephropathy had even higher sRAGE levels. While essential hypertension in the general population is connected with lower sRAGE levels [12], hypertension in dialysis patients is more related to overhydration than to vascular damage. In contrast to the study of Forbes et al. [29] where the angiotensin-converting enzyme inhibitor ramipril increased plasma sRAGE in diabetic rats and perindopril increased plasma sRAGE in patients with type 1 diabetes, our study did not demonstrate any difference in sRAGE levels between patients with and without antihypertensive therapy (especially when considering angiotensin-converting enzyme inhibitors or angiotensin II receptor 1 blockers). Contrary to our study, Nakamura et al. [30] showed, that the angiotensin II receptor 1 blocker telmisartan decreases serum levels of sRAGE in patients with essential hypertension (a study in 7 patients), which might reflect the reduced endothelial RAGE expression.

The level of sRAGE is associated with renal function, AGEs or inflammation, but it can also be influenced genetically. High sRAGE levels were demonstrated in two of the studied polymorphisms of the RAGE gene: –429 T/C (CC variant) and 2184 A/G (GG variant). The –429 T/C nucleotide is located on the gene promotor and is thus involved in the regulation of RAGE transcription [31]. The 2184 A/G nucleotide is located on intron 8. Also, sRAGE is produced by alternative splicing of RAGE mRNA which involves areas between introns 7 and 9 (exon 10 encodes the transmembrane domain) [10,13,32]. Intron 8 could hypothetically be situated within the regulatory element binding site and play a regulatory role [16]. In this context it should be mentioned that minor alleles in positions –429 (C) and 2184 (G) were significantly more frequent in patients with diabetic nephropathy than in the control group and were associated with acceleration of the onset of diabetic nephropathy [16].

Concerning sRAGE levels and survival, we did not demonstrate any difference in patients with sRAGE levels below and above the median, neither in the overall nor cardiovascular mortality. On the contrary, low circulating esRAGE was demonstrated as a predictor for cardiovascular mortality in a group of 206 end-stage renal disease patients [33]. For elucidation a higher number of patients should be observed for a longer period of time.

We conclude that in HD patients, sRAGE is increased due to the decreased renal function, which is a very strong determinant of sRAGE levels, and is inversely related to inflammation. The highest sRAGE levels are influenced genetically. In our study, sRAGE levels were not related to mortality of HD patients.



   Acknowledgements
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Acknowledgements
References
 
The authors are thankful to physicians and nurses from co-operating dialysis centres for technical assistance, especially to Dr Lachmanová (Department of Nephrology, 1st Faculty of Medicine and General University Hospital Prague), Prof. Dusilová-Sulková (Department of Medicine Strahov, 1st Faculty of Medicine and General University Hospital Prague), Dr Gorun (Ústí nad Orlicí), Dr Hobzek and Mrs Zd'ánská (Písek), Dr Suchanová and Dr Krízová (Tábor), and Dr Nydlová (Strakonice). The authors are equally thankful to laboratory staff for excellent laboratory skills, especially to Dr Soukupová, Mrs Miskovská, Mrs Dományová, Mrs Medová, Mrs Reháková and Mrs Pourová.

The study was supported by a grant Nucleus from the Elpida Foundation, by a grant from the Internal Grant Agency of the Czech Ministry of Health NR/8094-3 and by research project MSM0021620807 given by the Czech Ministry of Education.

Conflict of interest statement. None declared.



   References
Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Acknowledgements
 References
 

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Received for publication: 21. 7.06
Accepted in revised form: 17. 1.07


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