| 1. |
- Vanholder, Raymond, et al.
(författare)
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The role of EUTox in uremic toxin research.
- 2009
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Ingår i: Seminars in dialysis. - 0894-0959 .- 1525-139X. ; 22:4, s. 323-328
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Tidskriftsartikel (refereegranskat)abstract
- In this publication, we review the activities of the European Uremic Toxin Work Group (EUTox) in the field of uremic toxin research. Founded in 1999 under the umbrella of the European Society of Artificial Organs (ESAO), and active since 2000, this group focuses essentially on questions related to solute retention and removal during chronic kidney disease, and on the deleterious impact of those solutes on biological/biochemical systems. As of January 1, 2009, the group had met 28 times; it organized the third meeting, "Uremic Toxins in Cardiovascular Disease," which took place in October 2008 in Amiens, France. The current group is composed of 25 members belonging to 23 European research institutions. As of November 1, 2008, in total 69 papers had been published to which at least two different research groups belonging to EUTox have contributed in a collaborative effort. Of these, 40 papers were on original research and eight were specific EUTox reviews or position statements. A website (http://www.eutox.info) summarizes all relevant information concerning the work group. EUTox also developed an interactive uremic toxin database, where concentrations of known toxins are displayed, to be used by researchers in the field. In the future, EUTox intends to continue its focus on bench to bedside research with specific consideration of proteomics, metabonomics, secretomics, and genomics.
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| 2. |
- Carlsson, Axel C, et al.
(författare)
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Endostatin, cathepsin S, and cathepsin L, and their association with inflammatory markers and mortality in patients undergoing hemodialysis
- 2015
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Ingår i: Blood Purification. - : S. Karger AG. - 0253-5068 .- 1421-9735. ; 39:4, s. 259-265
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Tidskriftsartikel (refereegranskat)abstract
- Background/Aims: Although both endostatin and cathepsins S have been associated with higher mortality, data in patients with end-stage renal disease (ESRD) are scarce.Methods: A longitudinal cohort study of 207 prevalent patients undergoing hemodialysis.Results: Cathepsins S and L were associated with soluble receptors for tumor necrosis factor (sTNFR1 and sTNFR2, rho between 0.28 and 0.43, p < 0.001 for all). Weaker or absent associations between endostatin, cathepsins S and L were seen with other inflammatory biomarkers, that is, CRP, interleukin 6, pentraxin 3, and TNF. In Cox and Laplace regression models adjusted for age, sex, dialysis vintage, and diabetes: standard deviation increments of endostatin was associated with a lower mortality (hazard ratio 0.75, 95% confidence interval (CI) 0.57-0.98), and with 6.8 months longer median survival.Conclusions: The high levels of endostatin, cathepsins S and L, and their associations with sTNFR1 and sTNFR2 warrant further studies exploring mortality, and the angiogenic and inflammatory pathways in ESRD. (C) 2015 S. Karger AG, Basel
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| 3. |
- Carlsson, Axel C, et al.
(författare)
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High levels of soluble tumor necrosis factor receptors 1 and 2 and their association with mortality in patients undergoing hemodialysis
- 2015
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Ingår i: CardioRenal Medicine. - : S. Karger AG. - 1664-3828 .- 1664-5502. ; 5:2, s. 89-95
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Circulating soluble tumor necrosis factor receptors 1 and 2 (sTNFR1 and 5TNFR2) are associated with chronic kidney disease (CKD) progression in patients with CKD or diabetes, and with higher mortality. However, data in patients with end-stage renal disease are scarce. Therefore, we analyzed serum levels of sTNFR1 and sTNFR2 and investigated their association with inflammatory markers and mortality in dialysis patients. Research Design and Methods: This was a longitudinal cohort study of 207 prevalent patients (median age 66 years, 56% men) undergoing hemodialysis in Stockholm, Sweden. Demographics, clinical characteristics, including comorbidities and laboratory data, were obtained at baseline, together with prospective follow-up for mortality.Results: The median sTNFR1 and sTNFR2 levels were 17,680 ng/l [95% confidence interval (CI) 17,023-18,337] and 24,450 ng/l (95% CI 23,721-25,179), respectively. During a follow-up of 31 months (interquartile range, 21-38), 77 patients died. There was no association between the levels of sTNFRs and mortality in Cox regression models, and no consistent trend towards higher or lower mortality was seen in Laplace regression models. sTNFR1 and sTNFR2 levels were highly associated with other inflammatory markers including interleukin-6, pentraxin 3 and TNF-alpha. Conclusions:Prevalent hemodialysis patients have several-fold higher levels of sTNFRs compared to previous studies in CKD stage 4 patients. As no consistent association between TNFR and mortality was observed, clinical implications of measuring these receptors to predict outcome end-stage renal disease patients provide limited results.
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| 4. |
- Carrero, J.J., et al.
(författare)
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Telomere attrition is associated with inflammation, low fetuin : A levels and high mortality in prevalent haemodialysis patients
- 2008
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 263:3, s. 302-312
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Chronic kidney disease (CKD) predisposes to a 10- to 20-fold increased cardiovascular risk. Patients undergo accelerated atherogenesis and vascular ageing. We investigated whether telomere attrition, a marker of cell senescence, contributes to this increased mortality risk. METHODS: This is a cross-sectional study in prevalent haemodialysis patients [n = 175; 98 Males; median (range) age: 66 (23-86) years]. Biochemical markers of oxidative stress and inflammatory status were measured in relation to the patient's leucocyte telomere length. Overall mortality was assessed after a median of 31 (range 2-42) months. RESULTS: Telomere length was shorter in CKD men, despite women being older (average +/- SD 6.41 +/- 1.23 vs. 6.96 +/- 1.48 kb, P = 0.002). Telomere length was associated with age (rho = -0.18, P = 0.01), fetuin-A (rho = 0.26, P = 0.0004), high-sensitivity C-reactive protein (rho = -0.21, P = 0.005) and IL-6 (rho = -0.17, P = 0.02). In a multivariate logistic regression (pseudo r(2) = 0.14), telomere length was associated with age >65 years (odds ratio: 2.11; 95% CI: 1.10, 4.06), sex (2.01; 1.05, 3.86), fetuin-A (1.85; 0.97, 3.50) and white blood cell count (2.04; 1.02, 4.09). Receiver operating characteristic curves identified a telomere length < 6.28 kb as a fair predictor of mortality. Finally, reduced telomere length was associated with increased mortality, independently of age, gender and inflammation (likelihood ratio 41.6, P < 0.0001), but dependently on fetuin-A levels. CONCLUSION: Age and male gender seem to be important contributors to reduced telomere length in CKD patients, possibly via persistent inflammation. Reduced telomere length also contributes to the mortality risk of these patients through pathways that could involve circulating levels of fetuin-A.
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| 5. |
- Chambers, John C., et al.
(författare)
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Genetic loci influencing kidney function and chronic kidney disease
- 2010
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 42:5, s. 373-375
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Tidskriftsartikel (refereegranskat)abstract
- Using genome-wide association, we identify common variants at 2p12-p13, 6q26, 17q23 and 19q13 associated with serum creatinine, a marker of kidney function (P = 10(-10) to 10(-15)). Of these, rs10206899 (near NAT8, 2p12-p13) and rs4805834 (near SLC7A9, 19q13) were also associated with chronic kidney disease (P = 5.0 x 10(-5) and P = 3.6 x 10(-4), respectively). Our findings provide insight into metabolic, solute and drug-transport pathways underlying susceptibility to chronic kidney disease.
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| 6. |
- Ebert, Thomas, et al.
(författare)
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Insights in the regulation of trimetylamine N-oxide production using a comparative biomimetic approach suggest a metabolic switch in hibernating bears
- 2020
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Experimental studies suggest involvement of trimethylamine N-oxide (TMAO) in the aetiology of cardiometabolic diseases and chronic kidney disease (CKD), in part via metabolism of ingested food. Using a comparative biomimetic approach, we have investigated circulating levels of the gut metabolites betaine, choline, and TMAO in human CKD, across animal species as well as during hibernation in two animal species. Betaine, choline, and TMAO levels were associated with renal function in humans and differed significantly across animal species. Free-ranging brown bears showed a distinct regulation pattern with an increase in betaine (422%) and choline (18%) levels during hibernation, but exhibited undetectable levels of TMAO. Free-ranging brown bears had higher betaine, lower choline, and undetectable TMAO levels compared to captive brown bears. Endogenously produced betaine may protect bears and garden dormice during the vulnerable hibernating period. Carnivorous eating habits are linked to TMAO levels in the animal kingdom. Captivity may alter the microbiota and cause a subsequent increase of TMAO production. Since free-ranging bears seems to turn on a metabolic switch that shunts choline to generate betaine instead of TMAO, characterisation and understanding of such an adaptive switch could hold clues for novel treatment options in burden of lifestyle diseases, such as CKD.
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| 7. |
- Franco, Irene, et al.
(författare)
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Whole genome DNA sequencing provides an atlas of somatic mutagenesis in healthy human cells and identifies a tumor-prone cell type
- 2019
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Ingår i: Genome Biology. - : Springer Science and Business Media LLC. - 1465-6906 .- 1474-760X. ; 20:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The lifelong accumulation of somatic mutations underlies age-related phenotypes and cancer. Mutagenic forces are thought to shape the genome of aging cells in a tissue-specific way. Whole genome analyses of somatic mutation patterns, based on both types and genomic distribution of variants, can shed light on specific processes active in different human tissues and their effect on the transition to cancer. Results: To analyze somatic mutation patterns, we compile a comprehensive genetic atlas of somatic mutations in healthy human cells. High-confidence variants are obtained from newly generated and publicly available whole genome DNA sequencing data from single non-cancer cells, clonally expanded in vitro. To enable a well-controlled comparison of different cell types, we obtain single genome data (92% mean coverage) from multi-organ biopsies from the same donors. These data show multiple cell types that are protected from mutagens and display a stereotyped mutation profile, despite their origin from different tissues. Conversely, the same tissue harbors cells with distinct mutation profiles associated to different differentiation states. Analyses of mutation rate in the coding and non-coding portions of the genome identify a cell type bearing a unique mutation pattern characterized by mutation enrichment in active chromatin, regulatory, and transcribed regions. Conclusions: Our analysis of normal cells from healthy donors identifies a somatic mutation landscape that enhances the risk of tumor transformation in a specific cell population from the kidney proximal tubule. This unique pattern is characterized by high rate of mutation accumulation during adult life and specific targeting of expressed genes and regulatory regions.
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| 8. |
- Golembiewska, Edyta, et al.
(författare)
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Copeptin is independently associated with vascular calcification in chronic kidney disease stage 5
- 2020
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Ingår i: BMC Nephrology. - Stockholm : Karolinska Institutet, Dept of Clinical Science, Intervention and Technology. - 1471-2369.
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Tidskriftsartikel (refereegranskat)abstract
- Background: Vascular calcification (VC) is an independent predictor of cardiovascular disease (CVD) present in 30– 70% of patients with chronic kidney disease (CKD). Copeptin is a sensitive surrogate marker of arginine vasopressin (AVP), which is involved in many pathophysiologic processes in CKD. The aim of the present study was to explore the association of copeptin with VC in CKD stage 5. Methods: Copeptin was investigated in conjunction with living donor kidney transplantation in 149 clinically stable CKD stage 5 patients (CKD5), including 53 non-dialyzed (CKD5-ND) and 96 dialysis patients treated by peritoneal dialysis (PD) (n = 43) or hemodialysis (HD) (n = 53). We analyzed the association of copeptin with presence and extent of VC ascertained both histologically in biopsies from the inferior epigastric artery (n = 137) and by coronary artery calcification (CAC) score measured by computed tomography. Results: Patients with higher copeptin were older, had higher systolic blood pressure, higher prevalence of CVD and their preceding time on chronic dialysis was longer. In Spearman’s rank correlations (Rho), copeptin concentrations were significantly associated with CAC score (Rho = 0.27; p = 0.003) and presence of medial VC (Rho = 0.21; p = 0.016). Multivariate logistic regression analysis showed that 1-SD higher age, male gender, diabetes and 1-SD higher copeptin were significantly associated with the presence of moderate-extensive VC. Conclusions: High circulating levels of copeptin in CKD5 patients are independently associated with the degree of medial calcification ascertained by histology of arterial biopsies. Thus, plasma copeptin may serve as a marker of the uremic calcification process.
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| 9. |
- Hernandez, Leah, et al.
(författare)
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Blood-brain barrier and gut barrier dysfunction in chronic kidney disease with a focus on circulating biomarkers and tight junction proteins
- 2022
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Kidney failure and associated uraemia have implications for the cardiovascular system, brain, and blood-brain barrier (BBB). We aim to examine BBB disruption, by assessing brain-derived neurotropic factor (BDNF), neuron-specific enolase (NSE) levels, and gut-blood barrier (GBB) disruption by trimethylamine N-oxide (TMAO), in chronic kidney disease (CKD) patients. Additionally, endothelial tight-junction protein expressions and modulation via TMAO were assessed. Serum from chronic kidney disease (CKD) female and male haemodialysis (HD) patients, and controls, were used to measure BDNF and NSE by enzyme-linked immunosorbent assays, and TMAO by mass spectrometry. Immunofluorescent staining of subcutaneous fat biopsies from kidney transplant recipients, and controls, were used to measure microvascular expression of tight-junction proteins (claudin-5, occludin, JAM-1), and control microvasculature for TMAO effects. HD patients versus controls, had significantly lower and higher serum levels of BDNF and NSE, respectively. In CKD biopsies versus controls, reduced expression of claudin-5, occludin, and JAM-1 were observed. Incubation with TMAO significantly decreased expression of all tight-junction proteins in the microvasculature. Uraemia affects BBB and GBB resulting in altered levels of circulating NSE, BDNF and TMAO, respectively, and it also reduces expression of tight-junction proteins that confer BBB maintenance. TMAO serves as a potential candidate to alter BBB integrity in CKD.
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| 10. |
- Huang, Xiaoyan, et al.
(författare)
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Essential polyunsaturated fatty acids, inflammation and mortality in dialysis patients
- 2012
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Ingår i: Nephrology, Dialysis and Transplantation. - : Oxford University Press (OUP). - 0931-0509 .- 1460-2385. ; 27:9, s. 3615-3620
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Tidskriftsartikel (refereegranskat)abstract
- Background. Polyunsaturated fatty acids (PUFA) are essential nutrients with anti-inflammatory and cardioprotective properties. We investigated the association of essential dietary PUFA intake, reflected by plasma fatty acid composition, with inflammation and mortality in dialysis patients.Methods. We recruited 222 Swedish dialysis subjects (39% women) with median age of 57 years and average 12 months of dialysis vintage. Plasma phospholipid PUFA were assessed by gas-liquid chromatography. Overall mortality was assessed after 18.4 (10th-90th percentiles: 2.3-60) months of follow-up.Results. Linoleic acid (LA), Mead acid (MA), alpha-linolenic acid (ALA) and long-chain n-3 PUFA (LC n-3; the sum of eicosapentaenoic, docosapentaenoic and docosahexaenoic acids) represented 19.7, 0.26, 0.26 and 7.64% of all fatty acids in plasma, respectively. This may reflect an adequate n-3 PUFA intake. LA was negatively (beta = -0.21, P = 0.004) but MA positively (beta = 0.25, P < 0.001) associated with interleukin (IL)-6 in multivariate analyses. Neither ALA nor LC n-3 were independently associated with IL-6. During follow-up, 61 deaths and 115 kidney transplants occurred. Fully adjusted competing risk models showed that every percent increase in the proportion of plasma LA was associated with 12% reduction in mortality risk before transplantation (hazard ratio 0.88, 95% confidence interval 0.79-0.99). MA was directly associated with mortality. Neither ALA nor LC n-3 predicted outcome.Conclusions. The proportion of plasma phospholipid LA is inversely associated with IL-6 and all-cause mortality in Swedish dialysis patients. We raise the hypothesis that dialysis patients could benefit from increased intake of vegetable oils, the primary source of LA in the Western-type diet.
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