Current epigenetic aspects the clinical kidney researcher should embrace

Chronic kidney disease (CKD), affecting 10-12% of the world's adult population, is associated with a considerably elevated risk of serious comorbidities, in particular, premature vascular disease and death. Although a wide spectrum of causative factors has been identified and/or suggested, there is still a large gap of knowledge regarding the underlying mechanisms and the complexity of the CKD phenotype. Epigenetic factors, which calibrate the genetic code, are emerging as important players in the CKD-associated pathophysiology. In this article, we review some of the current knowledge on epigenetic modifications and aspects on their role in the perturbed uraemic milieu, as well as the prospect of applying epigenotype-based diagnostics and preventive and therapeutic tools of clinical relevance to CKD patients. The practical realization of such a paradigm will require that researchers apply a holistic approach, including the full spectrum of the epigenetic landscape as well as the variability between and within tissues in the uraemic milieu

CDKN2A/p16INK4a expression is associated with vascular progeria in chronic kidney disease

Patients with chronic kidney disease (CKD) display a progeric vascular phenotype linked to apoptosis, cellular senescence and osteogenic transformation. This has proven intractable to modelling appropriately in model organisms. We have therefore investigated this directly in man, using for the first time validated cellular biomarkers of ageing (CDKN2A/p16INK4a, SA-β-Gal) in arterial biopsies from 61 CKD patients undergoing living donor renal transplantation. We demonstrate that in the uremic milieu, increased arterial expression of CDKN2A/p16INK4a associated with vascular progeria in CKD, independently of chronological age. The arterial expression of CDKN2A/p16INK4a was significantly higher in patients with coronary calcification (p=0.01) and associated cardiovascular disease (CVD) (p=0.004). The correlation between CDKN2A/p16INK4a and media calcification was statistically significant (p=0.0003) after correction for chronological age. We further employed correlate expression of matrix Gla protein (MGP) and runt-related transcription factor 2 (RUNX2) as additional pathognomonic markers. Higher expression of CDKN2A/p16INK4a, RUNX2 and MGP were observed in arteries with severe media calcification. The number of p16INK4a and SA-β-Gal positive cells was higher in biopsies with severe media calcification. A strong inverse correlation was observed between CDKN2A/p16INK4a expression and carboxylated osteocalcin levels. Thus, impaired vitamin K mediated carboxylation may contribute to premature vascular senescence

Increased telomere attrition following renal transplantation: impact of anti-metabolite therapy

Background: The uremic milieu exposes chronic kidney disease (CKD) patients to premature ageing processes. The impact of renal replacement therapy (dialysis and renal transplantation [RTx]) or immunosuppressive treatment regimens on ageing biomarkers has scarcely been studied. Methods: In this study telomere length in whole blood cells was measured in 49 dialysis patients and 47 RTx patients close to therapy initiation and again after 12 months. Forty-three non-CKD patients were included as controls. Results: Non-CKD patients had significantly (P <= 0.01) longer telomeres than CKD patients. Telomere attrition after 12 months was significantly greater in RTx patients compared to dialysis patients (P = 0.008). RTx patients receiving mycophenolate mofetil (MMF) had a greater (P = 0.007) degree of telomere attrition compared to those treated with azathioprine. After 12 months, folate was significantly higher in RTx patients than in dialysis patients (P < 0.0001), whereas the opposite was true for homocysteine (P < 0.0001). The azathioprine group had lower levels of folate after 12 months than the MMF group (P = 0.003). Conclusions: The associations between immunosuppressive therapy, telomere attrition, and changes in folate indicate a link between methyl donor potential, immunosuppressive drugs, and biological ageing. The hypothesis that the increased telomere attrition, observed in the MMF group after RTx, is driven by the immunosuppressive treatment, deserves further attention

CDKN2A/p16INK4a expression is associated with vascular progeria in chronic kidney disease

Patients with chronic kidney disease (CKD) display a progeric vascular phenotype linked to apoptosis, cellular senescence and osteogenic transformation. This has proven intractable to modelling appropriately in model organisms. We have therefore investigated this directly in man, using for the first time validated cellular biomarkers of ageing (CDKN2A/p16INK4a, SA-β-Gal) in arterial biopsies from 61 CKD patients undergoing living donor renal transplantation. We demonstrate that in the uremic milieu, increased arterial expression of CDKN2A/p16INK4a associated with vascular progeria in CKD, independently of chronological age. The arterial expression of CDKN2A/p16INK4a was significantly higher in patients with coronary calcification (p=0.01) and associated cardiovascular disease (CVD) (p=0.004). The correlation between CDKN2A/p16INK4a and media calcification was statistically significant (p=0.0003) after correction for chronological age. We further employed correlate expression of matrix Gla protein (MGP) and runt-related transcription factor 2 (RUNX2) as additional pathognomonic markers. Higher expression of CDKN2A/p16INK4a, RUNX2 and MGP were observed in arteries with severe media calcification. The number of p16INK4a and SA-β-Gal positive cells was higher in biopsies with severe media calcification. A strong inverse correlation was observed between CDKN2A/p16INK4a expression and carboxylated osteocalcin levels. Thus, impaired vitamin K mediated carboxylation may contribute to premature vascular senescence

Longitudinal genome-wide DNA methylation changes in response to kidney failure replacement therapy

Chronic kidney disease (CKD) is an emerging public health priority associated with high mortality rates and demanding treatment regimens, including life-style changes, medications or even dialysis or renal transplantation. Unavoidably, the uremic milieu disturbs homeostatic processes such as DNA methylation and other vital gene regulatory mechanisms. Here, we aimed to investigate how dialysis or kidney transplantation modifies the epigenome-wide methylation signature over 12 months of treatment. We used the Infinium HumanMethylation450 BeadChip on whole blood samples from CKD-patients undergoing either dialysis (n = 11) or kidney transplantation (n = 12) and 24 age- and sex-matched population-based controls. At baseline, comparison between patients and controls identified several significant (PFDR < 0.01) CpG methylation differences in genes with functions relevant to inflammation, cellular ageing and vascular calcification. Following 12 months, the global DNA methylation pattern of patients approached that seen in the control group. Notably, 413 CpG sites remained differentially methylated at follow-up in both treatment groups compared to controls. Together, these data indicate that the uremic milieu drives genome-wide methylation changes that are partially reversed with kidney failure replacement therapy. Differentially methylated CpG sites unaffected by treatment may be of particular interest as they could highlight candidate genes for kidney disease per se

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention

Telomere attrition and elongation after dialysis therapy initiation in patients with end-stage renal disease

Aims: To analyze changes in telomere length (TL) after dialysis initiation. Methods: In 59 Japanese incident dialysis patients, associations between TL in peripheral blood leukocytes, inflammatory biomarkers and nutritional status at baseline and changes in TL during 1 year of dialysis, were investigated. Results: Whereas relative TL decreased by 8.6% (median 14.4%), TL elongation occurred in 16 patients (27%). Change in TL (ΔTL), defined as TL at 1 year minus TL at baseline, was associated with baseline TL (ρ = -0.70, p < 0.0001) and leukocyte count (ρ = 0.26, p = 0.044). In a logistic regression model, baseline TL (p < 0.0001) and leukocyte count (p = 0.047) were associated with ΔTL. Conclusions: TL shortening was observed in most incident dialysis patients. In 16 of the 59 patients, TL elongation occurred, possibly reflecting a more robust biological aging in patients whose naïve leukocytes may have undergone less proliferation to replace lost leukocytes

Is UCP2 Gene Polymorphism Associated With Decreased Resting Energy Expenditure in Nondialyzed Chronic Kidney Disease Patients?

Objective: the deletion/deletion (del/del) polymorphism of uncoupling protein 2 (UCP2) was associated with decreased energy expenditure in diabetic and obese patients. There is evidence of decreased resting energy expenditure (REE) in chronic kidney disease (CKD) patients not yet on dialysis. However, whether REE is associated with the UCP2 polymorphism was not previously investigated in this population. This study evaluated whether the del/del polymorphism of the UCP2 gene is associated with lower REE in nondialyzed CKD patients.Design: This was a cross-sectional study.Patients and Methods: Forty-four nondialyzed CKD patients (29 male; aged 52 12 years; creatinine clearance, 37 +/- 13 mL/min/1.73 m(2) [values are mean +/- SD unless otherwise noted]) were included. Their REE was assessed by indirect calorimetry, and body composition by bioelectrical impedance. High-sensitivity C-reactive protein (hs-CRP) was also evaluated. the insertion/deletion (ins/del) polymorphism of the UCP2 gene was determined in all participants. To test whether the deletion/deletion (del/del) polymorphism of the UCP2 gene was associated with lower REE, the REE of carriers of the del/del genotype (n = 24; group Del) was compared with that of carriers of the insertion and ins/del genotype (n = 20; group Ins).Main Outcome Measure: the main outcome measure was REE.Results: the REE of group Del was similar to that of the group Ins (1379 +/- 239 kcal/day vs. 1360 +/- 289 kcal/day, respectively, P = NS). This result was maintained even after the REE was adjusted for lean body mass by analysis of covariance. in addition, in a multiple-regression analysis using REE as the dependent variable, only lean body mass and hs-CRP were significant predictors of REE.Conclusion: the results suggest that the del/del polymorphism of the UCP2 gene is not associated with lower FEE in nondialyzed CKD patients. (C) 2008 by the National Kidney Foundation, Inc.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)undo de Auxilio aos Docente e Alunos da Universidade Federal de São PauloOswaldo Ramos Foundation (Brazil)Baxter Healthcare (Deerfield, IL)Universidade Federal de São Paulo, Div Nephrol, Dept Med, BR-04039000 São Paulo, BrazilKarolinska Inst, Div Baxter Novum, Dept Clin Sci Intervent & Technol, Stockholm, SwedenKarolinska Inst, Div Renal Med, Dept Clin Sci Intervent & Technol, Stockholm, SwedenUniversidade Federal de São Paulo, Postgrad Program Nutr, BR-04039000 São Paulo, BrazilPontificia Univ Catolica Parana, Div Biol Sci & Hlth, Maringa, Parana, BrazilKarolinska Inst, Dept Mol Med, Stockholm, SwedenUniversidade Federal de São Paulo, Div Nephrol, Dept Med, BR-04039000 São Paulo, BrazilUniversidade Federal de São Paulo, Postgrad Program Nutr, BR-04039000 São Paulo, BrazilWeb of Scienc