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- Kooman, JP, et al.
(författare)
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Inflammation and premature aging in advanced chronic kidney disease
- 2017
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Ingår i: American journal of physiology. Renal physiology. - : American Physiological Society. - 1522-1466 .- 1931-857X. ; 313:4, s. F938-F950
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Tidskriftsartikel (refereegranskat)abstract
- Systemic inflammation in end-stage renal disease is an established risk factor for mortality and a catalyst for other complications, which are related to a premature aging phenotype, including muscle wasting, vascular calcification, and other forms of premature vascular disease, depression, osteoporosis, and frailty. Uremic inflammation is also mechanistically related to mechanisms involved in the aging process, such as telomere shortening, mitochondrial dysfunction, and altered nutrient sensing, which can have a direct effect on cellular and tissue function. In addition to uremia-specific causes, such as abnormalities in the phosphate-Klotho axis, there are remarkable similarities between the pathophysiology of uremic inflammation and so-called “inflammaging” in the general population. Potentially relevant, but still somewhat unexplored in this respect, are abnormal or misplaced protein structures, as well as abnormalities in tissue homeostasis, which evoke danger signals through damage-associated molecular patterns, as well as the senescence-associated secretory phenotype. Systemic inflammation, in combination with the loss of kidney function, can impair the resilience of the body to external and internal stressors by reduced functional and structural tissue reserves, and by impairing normal organ crosstalk, thus providing an explanation for the greatly increased risk of homeostatic breakdown in this population. In this review, the relationship between uremic inflammation and a premature aging phenotype, as well as potential causes and consequences, are discussed.
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- le Poole, CY, et al.
(författare)
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"NEPP" peritoneal dialysis regimen has beneficial effects on plasma CEL and 3-DG, but not pentosidine, CML, and MGO
- 2012
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Ingår i: Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis. - : SAGE Publications. - 1718-4304 .- 0896-8608. ; 32:1, s. 45-54
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Tidskriftsartikel (refereegranskat)abstract
- Standard peritoneal dialysis (PD) solutions contain high levels of glucose and glucose degradation products (GDPs), both contributing to the formation of advanced glycation end products (AGEs). We studied the contribution to plasma GDP and AGE levels of 2 PD regimens that differ in glucose and GDP loads: high load [standard PD (sPD) using 4 glucose-lactate exchanges] and low load [1 amino acid exchange, 1 icodextrin exchange, and 2 glucose-bicarbonate/lactate exchanges (“NEPP”)]. Methods In a prospective crossover study (2 periods of 24 weeks), new continuous ambulatory PD patients were randomized to NEPP-sPD ( n = 23) or to sPD-NEPP ( n = 27). Results After the start of PD, absolute increases were observed in plasma levels of 3-deoxyglucosone (3-DG, 220.4 nmol/L, p < 0.0001) and in Nε-(carboxymethyl) lysine (CML) in plasma proteins (0.02 μmol/L CML per 1 mol/L lysine, p < 0.0001). During the first 6 weeks, 3-DG tended to increase more with sPD treatment (p = 0.08), and CML, with NEPP treatment (p = 0.002). In both groups, Nε-(carboxyethyl)lysine (CEL) in plasma proteins declined significantly with the start of PD. Treatment with NEPP resulted in higher levels of methylglyoxal (MGO) and lower levels of 3-DG and CEL. Pentosidine in the albumin fraction tended to increase less during NEPP treatment. Conclusions A low glucose and GDP PD regimen (NEPP) resulted in plasma levels of 3-DG and CEL that were lower than those with a glucose-based sPD regimen. Starting PD with NEPP was associated with a steeper increase in CML, and continuing treatment with NEPP resulted in higher MGO levels.
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- Porcu, E, et al.
(författare)
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Mendelian randomization integrating GWAS and eQTL data reveals genetic determinants of complex and clinical traits
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 3300-
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified thousands of variants associated with complex traits, but their biological interpretation often remains unclear. Most of these variants overlap with expression QTLs, indicating their potential involvement in regulation of gene expression. Here, we propose a transcriptome-wide summary statistics-based Mendelian Randomization approach (TWMR) that uses multiple SNPs as instruments and multiple gene expression traits as exposures, simultaneously. Applied to 43 human phenotypes, it uncovers 3,913 putatively causal gene–trait associations, 36% of which have no genome-wide significant SNP nearby in previous GWAS. Using independent association summary statistics, we find that the majority of these loci were missed by GWAS due to power issues. Noteworthy among these links is educational attainment-associated BSCL2, known to carry mutations leading to a Mendelian form of encephalopathy. We also find pleiotropic causal effects suggestive of mechanistic connections. TWMR better accounts for pleiotropy and has the potential to identify biological mechanisms underlying complex traits.
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