RAGE polymorphisms, renal function and histological finding at 12 months after renal transplantation

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Clinical Biochemistry 42 (2009) 347 – 352

RAGE polymorphisms, renal function and histological finding at 12 months after renal transplantation☆ Marta Kalousová a,⁎, Irena Brabcová b , Anna Germanová a , Marie Jáchymová a , Ivo Matl c , Oto Mestek d , Štěpán Bandúr b,c , Tomáš Zima a , Ondřej Viklický b,c a

Institute of Clinical Chemistry and Laboratory Diagnostics, First Faculty of Medicine and General University Hospital, Charles University, Karlovo nam. 32, 121 11 Prague 2, Czech Republic b Transplant Laboratory, Transplant Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic c Department of Nephrology, Transplant Center, Institute for Clinical and Experimental Medicine, Prague, Czech Republic d Institute of Chemical Technology, Prague, Czech Republic Received 30 May 2008; received in revised form 26 November 2008; accepted 10 December 2008 Available online 24 December 2008

Abstract Objectives: RAGE (receptor for advanced glycation end products) is involved in pathogenesis of many diseases. The aim of the study was to test whether polymorphisms of RAGE gene are associated with the outcome of kidney transplantation. Design and methods: Four polymorphisms of the RAGE gene (−429T/C, − 374T/A, Gly82Ser and 2184A/G) were assessed in 145 renal transplant recipients and their relationship to histological changes in 12 months protocol kidney graft biopsy and renal function was examined. Results: Genotype frequencies of each polymorphism corresponded to expected frequencies according to Hardy–Weinberg equilibrium. No differences between allelic and genotype frequencies among patients with normal histological findings, chronic allograft nephropathy and subclinical rejection were observed. Conclusion: This is the first study on polymorphisms of the RAGE gene in patients with the transplanted kidney. No association of RAGE selected gene polymorphisms with 12-months outcome of renal transplants was shown in study. © 2008 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. Keywords: Biopsy; Chronic allograft nephropathy; Kidney transplantation; Polymorphism; RAGE; Receptor for advanced glycation end products

Introduction The receptor for advanced glycation end products (RAGE) is involved in the pathogenesis of many diseases and their complications, including vascular disease, inflammatory diseases or diabetic complications [1,2]. RAGE was first characterized as receptor for advanced glycation end products (AGEs), however, it is a multi-ligand receptor which can bind also other mediators like proinflammatory S100 proteins/calgranulins, amphoterin or ☆

The study was supported by grant Nucleus from the Elpida Foundation and by the research projects MZO 0000VFN2005 (0000064165) and MZO 00023001. ⁎ Corresponding author. Fax: +42 0 224962848. E-mail addresses: [email protected], [email protected] (M. Kalousová).

amyloid β-peptide [3,4]. The detrimental effects on tissues mediated via RAGE are caused by generation of oxidative stress and up-regulation of inflammatory and pro-thrombotic pathways followed by tissue injury [3,5]. Soluble RAGE (sRAGE), its variant lacking the transmembrane domain, is a naturally occurring inhibitor of pathological effects mediated via RAGE [6] and a valuable biomarker [5]. Several studies have focused on the genetic background of RAGE (AGER — gene encoding RAGE) and have demonstrated that some gene polymorphisms are associated with amplification of the inflammatory response [7], with diabetic complications [8,9], or with coronary atherosclerosis [10,11]. Vascular damage plays a key role also in the outcome of patients suffering from the end stage renal disease (ESRD) including kidney transplant recipients. Our previous studies demonstrated elevation of sRAGE in dialysis patients [12,13],

0009-9120/$ - see front matter © 2008 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved. doi:10.1016/j.clinbiochem.2008.12.006

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its decrease after renal transplantation and correlation with early chronic vascular changes in the transplanted kidney [14]. Indeed, stimulation of RAGE leads to induction of specific cellular responses including release of profibrotic cytokines [15]. Additionally, low levels of sRAGE are associated with increased risk for mortality in renal transplant recipients [16]. As no study on the genetics of RAGE in patients after renal transplantation has been published we tested the association of the polymorphisms of the RAGE gene with clinical data and morphological changes in 12-months protocol kidney graft biopsy. Methods Patients 145 Caucasian patients who had undergone kidney transplantation (TPL) and were treated with tacrolimus or cyclosporin A, mycophenolat mofetil and steroids-based immunosuppression were included in this single center study. No antilymphocyte globulins' induction immunosuppression was used. One year after TPL a protocol biopsy of the kidney graft was performed in each patient. At the time of the protocol biopsy, all patients were in stable clinical status without clinical and laboratory signs of acute infection (CRP less than 8 mg/L) and had no acute cardiac problems. The study was approved by local Institutional Ethical Committee and all patients have given informed consent prior to entering the study. Samples Peripheral blood for DNA analysis was collected into tubes with EDTA (ethylene diamine tetraacetic acid) simultaneously with blood collection for routine laboratory examinations. Tubes were stored at − 4 °C and isolation of DNA was performed within 1 week and kept frozen at − 80 °C. RAGE polymorphisms — genotyping The gene encoding RAGE is located on chromosome 6p21.3 and comprises 11 exons (spanning 3.27 kb). Four single nucleotide polymorphisms (SNPs) of the RAGE gene − 429T/C (rs1800625), − 374T/A (rs1800624), Gly82Ser (557 G/A, rs 2070600) and 2184A/G (rs13209119) were determined from DNA extracted from a sample of peripheral blood. For amplification of the region containing the − 374T/A and − 429T/C polymorphisms, the following primers were used: forward primer 5′GGG GCA GTT CTC TCC TCA CT 3′ 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 3 U of restriction nucleases, AluI for − 429T/C and MfeI for − 374T/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 35 bp for the wild type allele − 374T and 250 bp for the mutated allele − 374A. After the digestion reaction with AluI fragments 250 bp for − 429T allele (wild type) and 88 + 162 bp for − 429C allele were detected. The Gly82Ser (557G/A) polymorphism in exon 3 of the RAGE gene was amplified by PCR using primers 5′GTA AGC GGG GCT CCT GTT GCA′3 and 5′GGC CAA GGC TGG GGT TGA AGG 3′ [17]. After digestion of PCR fragment (397 bp) with AluI we obtained fragments of 149 and 248 bp lengths for GG homozygous, but not 123, 26 and 248 bp as was reported in the publication. The digestion provided fragments of 149, 181 and 67 bp lengths for the AA homozygous. Our results were confirmed by sequencing analysis. Detection of 2184A/G polymorphism in intron 8 of RAGE gene was done according to Kankova et al. [17]. The PCR procedure was performed with all samples on two separate occasions. Other laboratory parameters Routine clinical chemistry methods were used for serum and urine analysis. Creatinine in serum was determined with Jaffé reaction, protein in urine was assessed with pyrogallol red, cholesterol was measured with cholesterol-oxidase and peroxidase methods, triacylglycerols with glycerolphosphate oxidase and peroxidase method and glucose with glucose oxidase and peroxidase method. Graft function was evaluated using calculation of glomerular filtration rate according to Cockcroft and Gault [18] and abbreviated MDRD (modification of diet in renal disease) formula [19]. All biopsies were done by a 14G tru-cut needle (Uni-Cut Nadeln, Angiomed) guided by ultrasound (Toshiba, Power

Table 1 Demographic and clinical parameters of the study cohort at the time of transplantation Parameter

Results

Number of patients (male/female) Age (years) Duration of dialysis treatment (days) PRA max (%) HLA A, B, DR mismatch Donor age (years) Etiology of renal failure (number of patients) Glomerulonephritis Interstitial nephritis Polycystic kidney disease Vascular nephrosclerosis Diabetic nephropathy Other

145 (95/50) 47.5 ± 13.1 481 (260–1071) 4.0 (0–20.0) 2.9 ± 1.3 45.0 ± 15.0 57 28 28 3 10 19

Data are expressed as mean ± SD (standard deviation), in case of high interindividual variability as median (inter-quartile range). Abbreviation: PRA max — maximal panel reactive antibodies.

M. Kalousová et al. / Clinical Biochemistry 42 (2009) 347–352 Table 2 Basic clinical and laboratory characteristics of the studied patients 1 year after kidney transplantation Parameter

Results

Number of patients (male/female) Race — Caucasian (male/female) BMI (kg/m2) Blood pressure (systolic/diastolic, mm Hg) Acute rejection within the 1 year after TPL Creatinine (μmol/L) GFR according to C-G formula (mL/s) GFR according to MDRD formula (mL/s) Proteinuria (g/day) Cholesterol (mmol/L) Triacylglycerols (mmol/L) Blood glucose (mmol/L) Graft biopsy finding (number of patients) Normal Subclinical rejection Chronic allograft nephropathy

145 (95/50) 145 (95/50) 26.5 ± 4.5 147 ± 20/88 ± 10 total number 63 in 43 patients 147.0 ± 89.4 1.05 ± 0.36 0.84 ± 0.29 0.6 ± 1.8 5.4 ± 1.1 2.4 ± 1.1 5.6 ± 0.7 70 15 60

Data are expressed as mean ± SD (standard deviation), in case of high interindividual variability as median (inter-quartile range). Abbreviations: BMI — body mass index, C-G — Cockcroft and Gault, GFR — glomerular filtration rate, MDRD — Modification of Diet in Renal Disease, TPL — transplantation.

Vision 6000). The renal tissue taken by core biopsy was used for routine histology performed by the standard method. Tissues were fixed in 10% formalin for 15–30 min and then processed in TPC 15 tissue processor (MEDITE Histotechnik, Germany). Four μm thick paraffin embedded tissue sections were stained with hematoxylin and eosin, periodic acid-Schiff (PAS), aldehyde-fuchsin orange G (AFOG), Sirius red with elastic stain and periodic acid silver-methenamine (PASM). Biopsy tissues were scored on the basis of the Banff 97 working classification [20] as the study and histological analysis was performed prior the new revision in 2007 was published. Subclinical rejection was defined as an acute rejection finding in protocol biopsy in patients with stable graft function. Statistical analysis The results of biochemical parameters are expressed as mean ± standard deviation, in an exceptional case of high inter-individual

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variability as median (inter-quartile range). Comparison of continuous variables was performed with one-way ANOVA (analysis of variance) or the Kruskal–Wallis test, and unpaired t-test or Wilcoxon test, as appropriate. χ2 or Fisher's exact test were used for comparison of proportions and for testing of Hardy Weinberg equilibrium. Single polymorphism associations were assessed using the Armitage test of trend and Fisher's exact test. Associations between parameters were determined using Pearson and Spearman correlation coefficients, according to the data distribution. Haplotype analysis was used for more detailed description. The tests used were two-sided and all results were considered as statistically significant at p b 0.05. These SNPs were chosen by post hoc analysis. The power of the study was calculated by DSTPLAN program. We calculated the sample size required to detect the effect of a polymorphism on the concentration of serum creatinine using the DSTPLAN software (http://linkage.rockefeller.edu/soft). For RAGE 2184 polymorphic allele, which has prevalence 33%, 60 carriers and 70 non-carriers were necessary to detect difference at least 36.8%. For the RAGE − 429 polymorphic allele, which has prevalence 21.5%, the same number of patients and controls allowed us to detect 33.4% difference in creatinine concentration. Assuming a 30% prevalence of acute rejection, the sample size allowed us to detect an association with an effect size of odds ratio ≥ 2.8 (RAGE 2184 polymorphism, frequency 0.33) or ≥ 3 (RAGE − 429 polymorphism, frequency 0.215). The calculations have been performed as two sided tests at 5% significance for 80% statistical power. Results Patients' characteristics The demographic and clinical parameters of this study cohort are shown in Table 1. Basic clinical and laboratory characteristics of the studied patients one year after transplantation are presented in Table 2. Table 3 depicts renal parameters in each patients' subgroup with different histological findings in the graft biopsy.

Table 3 Renal characteristics in each subgroup of transplanted patients with different histological findings in the graft biopsy Parameter

Histology Normal

SR

CAN

Number of patients (male/female) Creatinine (μmol/L) GFR according to C-G formula (mL/s) GFR according to MDRD formula (mL/s) Proteinuria (g/day)

70 126 ± 39 1.13 ± 0.37 0.92 ± 0.29 0.3 ± 0.5

15 128.6 (116–196) 0.99 ± 0.42 0.79 ± 0.34 0.5 ± 0.8

60 154 ± 44 ⁎⁎⁎ 0.98 ± 0.32 ⁎ 0.76 ± 0.24 ⁎⁎ 0.8 ± 2.8 ⁎

Data are expressed as mean ± SD (standard deviation), in case of high inter-individual variability as median (inter-quartile range). Abbreviations: CAN — chronic allograft nephropathy, C-G — Cockcroft and Gault, GFR — glomerular filtration rate, MDRD — Modification of Diet in Renal Disease, SR — subclinical rejection. ⁎ p b 0.05 CAN vs. normal. ⁎⁎ p b 0.005. ⁎⁎⁎ p b 0.001.

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Table 4 Allelic and genotype frequencies of studied polymorphisms of the gene for receptor for advanced glycation end products (RAGE) in transplanted patients — determined frequencies and expected genotype frequencies according to Hardy Weinberg equilibrium (HWE) RAGE polymorphism

Determined frequencies

− 429 T/C (%)

T 82.4, C 17.6 TT 66.2, TC 32.4, CC 1.4 T 63.4, A 36.6 TT 40.7, TA 45.5, AA 13.8 G 98.3, A 1.7 GG 96.6,GA 3.4, AA 0.0 A 66.3, G 33.7 AA 41.1,AG 50.4, GG 8.5

− 374 T/A (%) Gly82Ser (557G/A) (%) 2184 A/G (%)

HWE

TT 67.9, TC 29.0, CC 3.1 TT 40.3, TA 46.3, AA 13.4 GG 96.6, GA 3.4, AA 0.0 AA 44.0, AG 44.7,GG 11.3

Abbreviation: RAGE — receptor for advanced glycation end products. RAGE 2841A/G polymorphisms were not determined in 3 patients.

Allelic and genotype frequencies Allelic and genotype frequencies of studied polymorphisms of the gene for RAGE in transplanted patients are shown in Table 4. We were not able to determine the RAGE 2841A/G polymorphisms in 3 patients, probably due to some mutation in the restriction site. Detected genotype frequencies of each polymorphism corresponded to expected frequencies calculated according to Hardy–Weinberg equilibrium. Genotype/phenotype associations No differences between allelic and genotype frequencies among patients with normal histological findings, CAN and Table 5 Allelic and genotype frequencies of studied polymorphisms of the gene for receptor for advanced glycation end products (RAGE) in each subgroup of transplanted patients with different histological findings in the graft biopsy RAGE polymorphism Allelic and genotype frequencies in different histological findings − 429 T/C (%)

− 374 T/A (%)

Gly82Ser (557G/A) (%)

2184 A/G (%)

Normal T 79.3, C 20.7, TT 60.0, TC 38.6, CC 1.4 SR T 80.0, C 20.0, TT 66.7, TC 26.6, CC 6.7 OR = 1.62 (95% CI 0.78–3.38) CAN T 86.7, C 13.3, TT 73.3, TC 26.7, CC 0.0 OR = 0.58 (95% CI 0.28–1.19) Normal T 39.3, A 60.7, TT 37.2, TA 47.1, AA 15.7 SR T 33.3, A 66.7, TT 53.3, TA 26.7, AA 20.0 OR = 1.42 (95% CI 0.68–2.97) CAN T 34.2, A 65.8, TT 41.7, TA 48.3, AA 10.0 OR = 1.03 (95% CI 0.53–2.02) Normal G 98.6, S 1.4, GG 97.1,GA 2.9, AA 0.0 SR G 96.7, A 3.3, GG 93.3,GA6.7, AA 0.0 OR = 1.64 (95% CI 0.26–10.19) CAN G 98.3, A 1.7, GG 96.7,GA 3.3, AA 0.0 OR = 0.98 (95% CI 0.16–6.07) Normal A 63.4, G 36.6, AA 38.8,AG 49.3, GG 11.9 SR A 63.3, G 36.7, AA 26.7,AG 73.3, GG 0.0 OR = 1.86 (95% CI 0.87–3.99) CAN A 71.2, G 28.8, AA 49.1,AG 44.1, GG 6.8 OR = 0.58 (95% CI 0.29–1.15)

Respective odds ratios calculated for allelic models are included — polymorphic allele is taken as the risk allele. Abbreviations: CAN — chronic allograft nephropathy, OR — odds ratio, RAGE — receptor for advanced glycation end products, SR — subclinical rejection.

Table 6 Haplotype frequencies in each subgroup of transplanted patients with different histological findings in the graft biopsy (polymorphisms of RAGE gene − 429 T/C, −374T/A, 557G/A – Gly82Ser, 2184 A/G) Haplotype

Normal

SR

CAN

TAGA CAGA TAGG CAGG TAAA CAAA TAAG CAAG TTGA CTGA TTGG CTGG TTAA CTAA TTAG CTAG

17.47% 6.11% 10.04% 5.24% 0.44% 0.00% 0.00% 0.00% 22.27% 11.35% 15.72% 10.48% 0.44% 0.00% 0.44% 0.00%

15.22% 4.35% 8.70% 4.35% 2.17% 0.00% 0.00% 0.00% 23.91% 10.87% 17.39% 10.87% 2.17% 0.00% 0.00% 0.00%

19.05% 3.57% 8.33% 2.38% 0.60% 0.00% 0.00% 0.00% 30.36% 8.93% 17.26% 8.33% 1.19% 0.00% 0.00% 0.00%

Abbreviations: CAN — chronic allograft nephropathy, RAGE — receptor for advanced glycation end products, SR — subclinical rejection.

subclinical rejection were observed. These results with respective odds ratios calculated for allelic models are summarized in Table 5. There was no association between polymorphisms and the severity of CAN when separated to grades I–III. Additionally, we did not observe any differences among haplotype frequencies among the patients' subgroups with different histological findings (normal histological findings, CAN and subclinical rejection) as presented in Table 6. Concerning the relationship to renal clinical-chemistry parameters, neither genotypes nor haplotypes were associated with serum creatinine levels, glomerular filtration rate calculated according to Cockcroft and Gault formula or MDRD formula and proteinuria. Discussion This is the first study dealing with polymorphisms of the RAGE gene (− 429T/C, − 374T/A, Gly82Ser and 2184A/G) in patients with the transplanted kidney. No differences among patients with different histological findings in the graft in the 12 months protocol biopsy and no association with the graft function were shown. Our study, which was performed in a homogenous patients group of whom all underwent protocol biopsy finding, is limited by the relatively small sample size, which might have contributed to the negative finding of our study. The power of the study was about 20%. To achieve 80% power for respective analysis, patient sample size should be about 900, and for some analyses performed in our study, we would need 2500 patients or even 4900 patients, which is not realistic to get. Recent studies suggest a possible role of RAGE in transplant recipients. Blockade of RAGE attenuated ischemia and reperfusion injury to the liver in mice [21] and suppressed

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alloimmune reactions in vitro and delayed allograft rejection in murine heart transplantation [22]. Studies regarding kidney transplantation dedicated to the extracellular domain of this receptor, sRAGE, and described a correlation of sRAGE to arteriolar hyaline thickening in the graft [14] and an association of low levels of sRAGE with increased risk for mortality in renal transplant recipients [16]. Although sRAGE was not measured in this study, we have demonstrated significantly higher sRAGE levels in mutated homozygous − 429CC and 2184GG in our previous study in hemodialysis patients [13]. Having looked at the allelic and genotype frequencies is has to be mentioned that transplanted patients have significantly higher frequency of the mutated G allele (33.7% in transplanted patients, 20.0% in a non-selected group of hemodialysis patients and 18.5% in healthy controls, p b 0.001) which is connected with higher sRAGE levels with better prognosis according to the above mentioned study [16]. Vascular changes within the transplanted kidney and renal function in the first year after kidney transplantation have been suggested to predict long-term kidney graft outcome. Despite this fact, involvement of RAGE in vascular diseases and its enhanced expression in chronic kidney disease [23], no other study apart from ours focusing at RAGE genetics in transplanted patients is available at present. On the other hand, several studies on RAGE polymorphisms were performed in patients with cardiovascular disease or diabetic nephropathy. The A allele of the − 374T/A polymorphism, which was examined also in our study, was associated with decreased risk for cardiovascular disease in the general population or in diabetic patients [8,10,11,24–26]. The Gly82Ser polymorphism was not associated with cardiovascular disease in the Framingham offspring study [27] as well as in patients with rheumatoid arthritis [28]. On contrary, the minor 82A allele containing genotypes were associated with significantly decreased risk of coronary artery disease [29]. Concerning diabetes and diabetic nephropathy, 82A allele was described as a risk allele for developing advanced nephropathy in type 1 diabetics [30], however, in type 2 diabetics earlier onset of diabetic nephropathy was associated with − 429C and 2184G alleles [9]. Additionally, 2184A/G polymorphism showed a significant association with diabetic nephropathy in type 2 diabetes in single-locus as well as in multi-locus analysis [31]. Another study has shown an association between the RAGE − 374T/A homozygous AA genotype and lower albumin excretion in type 1 diabetics with poor metabolic control [8]. A more recent study demonstrated an association of the A allele of the − 374T/A polymorphism and type 1 diabetes. The − 374A allele containing genotypes were also more frequent in patients with diabetic nephropathy and diabetic retinopathy. On the other hand, the TT genotype was more frequent in diabetic nephropathy in type 2 diabetic patients with HbA1c values bellow the median [32]. Both − 374T/A and − 429T/C polymorphisms are functional and mutated alleles increase transcriptional activities [33] which further supports their pathophysiological relevance. Concerning other polymorphisms of the RAGE gene, the 63 bp deletion (from bp − 407 to bp − 345) in the promoter of RAGE seemed to

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be protective from diabetic nephropathy in patients with type 2 diabetes [34] and the minor allele of C-1152A, a polymorphism located in the promoter region of the RAGE gene, was associated with a longer duration of nephropathy-free diabetes in type 1 diabetics [35]. We suppose, that the 63 bp deletion was not present in our samples as in the position of the deletion, we had a reverse primer for the studied polymorphisms located in the promoter (− 429T/C and − 374T/A). In case of a deletion, annealing would not occur and we have always got a PCR product. The prior literature data stimulated as to perform the present study and some relationship of RAGE gene polymorphisms was supposed. The above mentioned polymorphisms were chosen for the study as they have shown their relevance in other related diseases. Our results do not exclude possible associations of RAGE gene polymorphisms with extreme phenotypes such as graft failure soon after transplantation. These patients were not studied as there was no reason to perform protocol biopsy 1 year after transplantation and the study is based on histological findings. Additionally, small number of patients with diabetic nephropathy in our study population did not enable us to look at the association with diabetes. In conclusion, this is the first study dealing with polymorphisms of the RAGE gene in patients with the transplanted kidney. Despite the role of RAGE in many diseases including vascular or inflammatory ones, no association of its selected gene polymorphisms with CAN was shown in our study. Conflict of interest statement None declared.

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