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ABSTRACT: Elevated systemic pentraxin 3 (PTX3) levels appear to be a powerful marker of inflammatory status and a superior outcome predictor in patients with chronic kidney disease (CKD). As previous data imply that PTX3 is involved in vascular pathology and that adipose tissue mass may influence circulating PTX3 levels, we aimed to study the importance of adipose tissue expression of PTX3 in the uremic milieu and its relation to endothelial dysfunction parameters. Plasma PTX3 and abdominal subcutaneous adipose tissue (SAT) PTX3 mRNA levels were quantified in 56 stage 5 CKD patients (median age 57 [range 25-75] years, 30 males) and 40 age and gender matched controls (median age 58 [range 20-79] years, 27 males). Associations between PTX3 measures and an extensive panel of clinical parameters, including surrogate markers of endothelial function, were assessed. Functional ex vivo studies on endothelial status and immunohistochemical staining for PTX3 were conducted in resistance subcutaneous arteries isolated from SAT. SAT PTX3 mRNA expression correlated with plasma PTX3 concentrations (rho = 0.54, p = 0.0001) and was increased (3.7 [0.4-70.3] vs. 1.2 [0.2-49.3] RQ, p = 0.02) in CKD patients with cardiovascular disease (CVD), but was not significantly different between patients and controls. The association to CVD was lost after adjustments. SAT PTX3 mRNA levels were independently correlated to asymmetric dimethylarginine and basal resistance artery tone developed after inhibition with nitric oxide synthase and cyclooxygenase (rho = -0.58, p = 0.002). Apparent positive PTX3 immunoreactivity was observed in both patient and control arteries. In conclusion, fat PTX3 mRNA levels are associated with measures of endothelial cell function in patients with CKD. PTX3 may be involved in adipose tissue-orchestrated mechanisms that are restricted to the uremic milieu and modify inflammation and vascular complications in CKD patients.
PLoS ONE 01/2013; 8(5):e63493. · 4.09 Impact Factor
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ABSTRACT: The tools of modern molecular biology are evolving rapidly, resulting in vastly more efficient approaches to illuminating human genetic variations and their effects on common multifactorial disorders such as chronic kidney disease (CKD). Indeed, candidate gene association studies and genome-wide association studies (GWASs) have generated novel genetic variants in previously unrecognized biological pathways, highlighting disease mechanisms with a potential role in CKD etiology, morbidity and mortality. Nephrologists now need to find ways to make use of these advancements and meet the increasingly stringent requirements for valid study design, data handling and interpretation of genetic studies. Adding to our prior article in this journal, which introduced the basics of genotype-phenotype association studies in CKD, this second article focuses on how to ascertain robust and reproducible findings by applying adequate methodological and statistical approaches to genotype-phenotype studies in CKD populations. Moreover, this review will briefly discuss genotype-based risk prediction, pharmacotherapy, drug target identification and individualized treatment solutions, specifically highlighting potentially important findings in CKD patients. This increased knowledge will hopefully facilitate the exciting transition from conventional clinical medicine to gene-based medicine. However, before this can be accomplished, unsolved issues regarding the complex human genetic architecture as well technical and clinically oriented obstacles will have to be overcome. Additionally, new policies and standardized risk evaluations for genetic testing in the clinical setting will have to be established to guarantee that CKD patients are provided with high-quality genotype-guided counseling that will help to improve their poor outcomes.
Journal of nephrology 10/2012; · 1.65 Impact Factor
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ABSTRACT: In spite of extensive research resulting in major advances in renal care including technological improvements of dialysis, the poor outcome of chronic kidney disease patients has only marginally been improved since the 1980s. It has thus become clear that new strategies are needed to move forward. There are now great expectations that increased knowledge about genetic characteristics combined with other biological markers will identify pathophysiological pathways involved in the initiation and progression of renal damage and that this in turn will help define tools for early disease intervention and personalized treatment strategies. Already, new methodologies have made it possible to study the heritable component of many kidney diseases, and it is probable that DNA-based diagnostics will be performed on a regular basis for many conditions in the near future. This article discusses basic genetic concepts and highlights some of the novel approaches available for genome-wide genetic analyses. We hope that it may serve as an introduction to the research field of what we call "nephrogenetics." A second article in this series will focus on the interpretation and evaluation of genetic association studies and how to make use of this information to improve patient care and outcomes.
Journal of nephrology 03/2012; 25(2):141-9. · 1.65 Impact Factor
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Philippe A Melas,
Maria Rogdaki,
Andreas Lennartsson,
Karl Björk,
Hongshi Qi, Anna Witasp,
Martin Werme,
Gregers Wegener,
Aleksander A Mathé,
Per Svenningsson,
Catharina Lavebratt
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ABSTRACT: P11 (S100A10) has been associated with the pathophysiology of depression both in human and rodent models. Different types of antidepressants have been shown to increase P11 levels in distinct brain regions and P11 gene therapy was recently proven effective in reversing depressive-like behaviours in mice. However, the molecular mechanisms that govern P11 gene expression in response to antidepressants still remain elusive. In this study we report decreased levels of P11, associated with higher DNA methylation in the promoter region, in the prefrontal cortex of the Flinders Sensitive Line (FSL) genetic rodent model of depression. This hypermethylated pattern was reversed to normal, as indicated by the control line, after chronic administration of escitalopram (a selective serotonin reuptake inhibitor; SSRI). The escitalopram-induced hypomethylation was associated with both an increase in P11 gene expression and a reduction in mRNA levels of two DNA methyltransferases that have been shown to maintain DNA methylation in adult forebrain neurons (Dnmt1 and Dnmt3a). In conclusion, our data further support a role for P11 in depression-like states and suggest that this gene is controlled by epigenetic mechanisms that can be affected by antidepressant treatment.
The International Journal of Neuropsychopharmacology 06/2011; 15(5):669-79. · 4.58 Impact Factor
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ABSTRACT: Low levels of circulating fetuin-A are associated with increased mortality in dialysis patients. This study aimed to examine a potential causative role for fetuin-A on mortality by investigating whether a functional polymorphism in the alpha2-Heremans-Schmid glycoprotein (AHSG) gene associates with mortality, and by estimating the causative effect of fetuin-A levels on mortality using a Mendelian randomization design.
One thousand and forty-three incident dialysis patients were genotyped for the Thr256Ser polymorphism (rs4918) and followed up for 5 years; in 549 patients, serum fetuin-A levels were measured.
Carriers of a serine allele displayed lower fetuin-A levels (-0.07 g/L per allele, P < 0.001). A small increased mortality risk was observed for the Thr/Ser and Ser/Ser genotype compared with the Thr/Thr genotype (HR 1.03, 95% CI 0.83-1.28 and HR 1.10, 95% CI 0.78-1.55, respectively). Using the AHSG genotype as an instrumental variable, the causative HR of fetuin-A levels on mortality was estimated as 1.01 per 0.1-g/L increase. Inflammation and diabetes partially modified the association of fetuin-A levels with outcome.
The Thr256Ser polymorphism was weakly associated with mortality, and no causative effect of fetuin-A levels on this outcome was observed. Other risk factors, including inflammation and diabetes, might lead to lower fetuin-A levels, and/or modify the effect of low fetuin-A on mortality in end-stage renal disease patients.
Nephrology Dialysis Transplantation 01/2011; 26(1):239-45. · 3.40 Impact Factor
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ABSTRACT: Premature vascular calcification (or rather ossification) significantly contributes to morbidity and mortality in patients with chronic kidney disease stage 5 (CKD-5) and is linked to dysregulation of bone remodelling proteins. Recent evidence of a cross-talk between bone and fat tissue urged us to investigate whether the calcification/ossification-associated factors osteoprotegerin (OPG) and alpha-2-HS-glycoprotein (AHSG) are expressed in human uremic subcutaneous adipose tissue (SAT) and if the expression differs from nonuremic SAT.
Abdominal SAT biopsies were obtained from 38 patients with CKD-5 [16 women, 58 (22-73) years old] during the surgical insertion of a peritoneal dialysis catheter and 20 controls [11 females, 56 (40-77) years old] undergoing elective hernia repair or laparoscopic cholecystectomy. Real-time polymerase chain reaction (PCR) quantifications were performed followed by immunohistochemical staining and serum protein concentration measurements. Relative mRNA expression and protein concentrations were evaluated together with clinical parameters. An additional 59 patients with CKD-5 were included for replication of statistical analyses.
OPG but not AHSG mRNAs were detected in SAT, which were also positively immunolabelled for OPG. OPG mRNA levels were reduced (P = ·0001) and serum OPG concentrations were elevated (P < 0·0001), both about twofold, in patients compared to controls. Circulating OPG increased in proportion to BMI.
Human SAT expresses OPG but not AHSG, and OPG expression is reduced in patients with CKD-5 when compared to controls, despite increased circulating protein levels.
European Journal of Clinical Investigation 12/2010; 41(5):498-506. · 3.02 Impact Factor
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ABSTRACT: The mechanisms behind postoperative insulin resistance and impaired glucose utilization are not fully understood.
In this study, we aimed to specifically evaluate the transcription profile of genes in the insulin and adipokine signaling pathways in sc and omental adipose tissue after surgical injury.
Relative expression of 21 target genes was analyzed in both sc and omental adipose tissue sampled at the beginning and at the end of operation.
The study was conducted at a university-affiliated hospital.
Twelve nondiabetic patients [seven females; age, 65 (range, 46-72) yr; body mass index, 24.8 (16.5-29.8) kg/m(2)] undergoing major abdominal surgery were included.
The changes in mRNA levels were analyzed.
After surgery, both sc and omental adipose tissue mRNA levels of genes involved in the IL6 and nicotinamide phosphoribosyltransferase pathways were increased, whereas mRNA levels of insulin receptor substrate 1 and adiponectin were reduced (P < 0.05). TNF pathway genes were differently regulated between sc and omental adipose tissue, and glucose transporter 4 mRNA levels were decreased only in omental adipose tissue.
The transcriptional output of pivotal inflammatory and insulin signaling pathway genes is altered after surgery, and this pattern differs between different fat depots. This could be of importance for the metabolic aberrations associated to postsurgical complications, such as insulin resistance and hyperglycemia.
The Journal of clinical endocrinology and metabolism 05/2010; 95(7):3460-9. · 6.50 Impact Factor
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Juan J Carrero, Anna Witasp,
Peter Stenvinkel,
Abdul R Qureshi,
Olof Heimbürger,
Peter Bárány,
Mohamed E Suliman,
Björn Anderstam,
Bengt Lindholm,
Louise Nordfors,
Martin Schalling,
Jonas Axelsson
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ABSTRACT: Anorexia is a common complication of chronic kidney disease (CKD), while novel animal and human data suggest a role for visfatin in regulating feeding behavior. We hypothesized that increased visfatin levels in CKD patients may be involved in the regulation of appetite and nutrient homeostasis.
This is a cross-sectional study where circulating visfatin levels were analysed in 246 incident CKD stage 5 patients starting dialysis therapy. The associations between visfatin (enzyme-linked immunosorbent assay, ELISA) and anthropometric and biochemical nutritional status, self-reported appetite, fasting serum amino acids (high-performance liquid chromatography) and circulating cytokine levels (ELISAs) were assessed. We also performed genotyping (Pyrosequencing(R)) of two polymorphisms (rs1319501 and rs9770242) in the visfatin gene.
Serum visfatin concentrations were not associated with either body mass index or serum leptin. Across groups with worsening appetite, median visfatin levels were incrementally higher (P < 0.05). With increasing visfatin tertiles, patients proved to be more often anorectic (P < 0.05) and to have incrementally lower serum albumin, cholesterol and triglycerides as well as lower essential and non-essential serum amino acids (P < 0.05 for all). A polymorphism in the visfatin gene was associated with increased circulating visfatin levels and, at the same time, a higher prevalence of poor appetite (P < 0.05 for both).
Our study suggests novel links between visfatin and anorexia in CKD patients. Based on recent studies, we speculate that high visfatin in CKD patients may constitute a counter-regulatory response to central visfatin resistance in uremia. Future studies should examine a putative role of visfatin as a regulator of nutrient homeostasis in uremia.
Nephrology Dialysis Transplantation 11/2009; 25(3):901-6. · 3.40 Impact Factor
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ABSTRACT: Postoperative insulin resistance, resulting in hyperglycemia, is strongly associated to morbidity and mortality in surgical patients but the underlying mechanisms are unclear. As increasing data suggests a link between inflammation and insulin resistance, we aimed to evaluate if the expression of inflammatory and insulin signaling genes is regulated in skeletal muscle during surgery.
Eight patients (4 females, 63 [46-69] years, body mass index 25.5 [16.5-29.8]kg/m(2)) undergoing major abdominal surgery were included. Biopsies from m. rectus abdominis were obtained at the beginning and at the end of the operation. mRNA levels of 45 genes were analyzed.
The time elapsed between the two biopsies was 224 (198-310) min. An increased (p<0.05) expression was noted for genes encoding both inflammatory mediators, such as interleukin 6, tumor necrosis factor, and nuclear factor of kappa light polypeptide gene enhancer in B cells, and metabolic regulators, such as peroxisome proliferator-activated receptor delta, while the analysis did not detect significant expression changes of the insulin signaling pathway genes.
The observed gene expression changes in skeletal muscle during surgery occurred mainly in inflammatory pathways, suggesting a possible role for inflammation in the development of postoperative insulin resistance.
Clinical nutrition (Edinburgh, Scotland) 04/2009; 28(3):291-8. · 3.27 Impact Factor
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ABSTRACT: As the modern nephrology community continues to be burdened with growing numbers of patients with end-stage renal disease (ESRD) and exceptionally high mortality rates, it is obvious that progress in the development of preventive and therapeutic strategies has not been sufficient. This urges nephrologists to focus on the underlying mechanisms for ESRD morbidity and mortality, and in particular on cardiovascular disease (CVD), which is the major contributor to premature death in this patient group. The high prevalence of inflammation, vascular ossification, and oxidative stress in ESRD predisposes these patients to CVD. Because genetic risk factors may modulate the pathophysiologic response, genotype-phenotype association studies may provide ways of predicting individual disease progression and may shed some light on key regulatory pathways. Indeed, recent genetic association studies show that polymorphisms in candidate genes related to inflammatory signaling, vascular ossification, and oxidative stress response influence the uremic phenotype. DNA polymorphisms may also be used as nonconfounded tools in observational studies conducted to test causality, as stated by the mendelian randomization approach. To date, the collection of genetic data is no longer a limitation because genetic information is easily accessible in public databases and high-throughput genotyping technologies are available. Advanced bioinformatic tools are now warranted to facilitate the integration of accumulating genetic information with clinical and biochemical end points and, finally, to implement genotype-phenotype data in the care of patients with renal failure to better identify patients at high risk and to design novel personalized therapeutic and preventive strategies.
Journal of Renal Nutrition 02/2007; 17(1):17-22. · 1.57 Impact Factor
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Jonas Axelsson, Anna Witasp,
Juan Jesús Carrero,
Abdul R Qureshi,
Mohamed E Suliman,
Olof Heimbürger,
Peter Bárány,
Bengt Lindholm,
Anders Alvestrand,
Martin Schalling,
Louise Nordfors,
Peter Stenvinkel
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ABSTRACT: Visfatin, also known as pre-B-cell colony-enhancing factor 1 (PBEF-1), recently was shown to be secreted from adipocytes and have insulin-mimetic properties in mice. Because renal failure per se is associated with both increased levels of circulating peptides and marked insulin resistance, even in the absence of diabetes mellitus, we hypothesized that visfatin could be a factor linking inflammation, kidney disease, and insulin resistance in this patient group.
Altogether, we studied 189 patients with chronic kidney disease (CKD), comprising 149 patients with CKD stage 5 (glomerular filtration rate [GFR] < 15 mL/min; mean, 7 +/- 2 mL/min [<0.25 mL/s; mean, 0.12 +/- 0.03 mL/s]; 61% men; mean age, 54 +/- 12 years) and 40 patients with CKD stages 3 to 4 (GFR, 15 to 60 mL/min; mean, 33 +/- 21 mL/min [0.25 to 1.00 mL/s; mean, 0.55 +/- 0.35 mL/s]; 72% men; age, 59 +/- 15 years). We compared these with 30 randomly selected population controls (mean GFR, 85 +/- 16 mL/min [1.42 +/- 0.27 mL/s]; 69% men; age, 64 +/- 11 years). Serum visfatin was measured by using commercially available enzyme-linked immunosorbent assay, and we also performed genotyping of 3 verified polymorphisms in the visfatin gene (-423A/G, -1001T/G, and -1535C/T). Body fat was estimated by using dual-energy x-ray absorptiometry.
Serum visfatin levels were greater in patients with CKD stage 5 (41.3 +/- 18.0 ng/mL) than in those with CKD stages 3 to 4 (34.0 +/- 9.8 ng/mL; P < 0.01 versus CKD stage 5) or healthy controls (29.3 +/- 8.1 ng/mL; P < 0.0001). However, there were no significant differences between patients with and without diabetes, and the significant differences in circulating visfatin levels between genotypes disappeared after adjustment for differences in age, sex, GFR, and serum albumin level. In univariate analysis, visfatin level correlated with levels of GFR (rho = -0.22; P = 0.001), interleukin 6 (IL-6; rho = 0.17; P = 0.01), high-sensitivity C-reactive protein (rho = 0.14; rho < 0.05), and soluble vascular cell adhesion molecule 1 (sVCAM-1; rho = 0.39; P < 0.0001), but not total or truncal fat mass, insulin resistance, or hemoglobin A(1c) level. High plasma visfatin level predicted mortality in patients with CKD, also after adjustment for age and sex (likelihood ratio, 18.2; P < 0.0001), but not after additional correction for GFR, sVCAM-1, serum albumin, and serum IL-6 levels.
Circulating levels of the cytokine visfatin/PBEF-1 are influenced by renal function, but are not associated with fat mass or surrogate markers of insulin resistance in patients with CKD. Visfatin was associated independently with level of sVCAM-1, a marker of endothelial damage.
American Journal of Kidney Diseases 02/2007; 49(2):237-44. · 5.43 Impact Factor
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Jonas Axelsson,
Holger Jon Møller, Anna Witasp,
Abdul Rashid Qureshi,
Juan Jesus Carrero,
Olof Heimbürger,
Peter Bárány,
Anders Alvestrand,
Bengt Lindholm,
Søren K Moestrup,
Peter Stenvinkel
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ABSTRACT: Recently, adipose tissue was shown to contain macrophages capable of contributing to systemic inflammation and cardiovascular disease (CVD). Here, we investigate this putative relationship in patients with chronic kidney disease (CKD) by using the novel macrophage marker soluble (s)CD163.
One hundred twenty patients with CKD stage 5 (mean glomerular filtration rate [GFR], 7 +/- 1 mL/min [0.12 +/- 0.02 mL/s; mean age, 53 +/- 1 years; 65% men), 38 patients with CKD stages 3 to 4 (mean GFR, 33 +/- 3 mL/min [0.55 +/- 0.05 mL/s]; mean age, 67 +/- 2 years; 68% men), and 28 healthy controls (mean GFR, 89 +/- 3 mL/min [1.48 +/- 0.05 mL/s]; mean age, 63 +/-2 years; 69% men) were characterized post hoc with a follow-up of up to 5 years (mean, 47 +/- 1 months). sCD163 levels, body composition (dual-energy x-ray absorptiometry), clinical parameters, and levels of circulating inflammatory markers (enzyme-linked immunosorbent assay) were assessed at baseline and, in a subset population, after 1 year of dialysis therapy (hemodialysis, n = 19; peritoneal dialysis, n = 30).
sCD163 level increased in patients with both severe (median, 4.3 mg/L; range, 1.3 to 23.4 mg/L) and moderate (median, 3.6 mg/L; range, 1.6 to 9.8 mg/L) CKD compared with controls (median, 2.6 mg/L; range, 0.8 to 7.6 mg/L; P < 0.001). Furthermore, sCD163 levels correlated with both truncal (rho = 0.17; P < 0.05) and total (rho = 0.17; P < 0.05) fat mass, as well as with all measured markers of inflammation and endothelial adhesion molecules. After 1 year, patients who increased body fat mass (average, 11% +/- 5% versus -5% +/- 5%; P < 0.05) also showed a significant increase in sCD163 levels (median, 2.2 versus -0.97 mg/L; P < 0.01). Finally, patients with sCD163 levels greater than 4.0 mg/L had a statistically significantly worse outcome than patients with sCD163 levels less than this value, even after adjustment for age, sex, and diabetes mellitus (chi-square = 19.98; P < 0.001). However, this effect was lost after adjustment for either inflammation or CVD.
We show that increasing fat mass is associated with increasing levels of sCD163, a circulating marker of macrophages also associated with inflammatory biomarkers. We thus hypothesize that adipose tissue macrophages may have a role in the proinflammatory state observed in patients with renal disease. Finally, we propose the term "uremic-metabolic syndrome" to describe this state of increased adipose tissue signaling in patients with uremia, a phenomenon that may share some characteristics with the metabolic syndrome of obesity.
American Journal of Kidney Diseases 01/2007; 48(6):916-25. · 5.43 Impact Factor
