We performed a genome-wide association study (GWAS) of IgA nephropathy (IgAN), the most common form of glomerulonephritis, with discovery and follow-up in 20,612 individuals of European and East ...Asian ancestry. We identified six new genome-wide significant associations, four in ITGAM-ITGAX, VAV3 and CARD9 and two new independent signals at HLA-DQB1 and DEFA. We replicated the nine previously reported signals, including known SNPs in the HLA-DQB1 and DEFA loci. The cumulative burden of risk alleles is strongly associated with age at disease onset. Most loci are either directly associated with risk of inflammatory bowel disease (IBD) or maintenance of the intestinal epithelial barrier and response to mucosal pathogens. The geospatial distribution of risk alleles is highly suggestive of multi-locus adaptation, and genetic risk correlates strongly with variation in local pathogens, particularly helminth diversity, suggesting a possible role for host-intestinal pathogen interactions in shaping the genetic landscape of IgAN.
Abstract
Background and Aims
Before evaluating any ESA treatment, International guidelines (NICE-2015, KDIGO-2012, ERBP–2013) suggest to administer iron first to patients with iron deficiency anemia ...and not still on ESA therapy. Moreover anemic CKD patients treated with ESA should be iron supplemented (unless ferritin is> 800 mcg/l) to maximize the benefits of ESAs.
A recent retrospective study of switching iron sucrose to ferric carboxymaltose (FCM), conducted by Hofman et al., showed a better control of iron status in hemodialysis (HD) patients. New generation drugs, like carboxymaltose, may change the iron administration methods on dialysis, due to their different properties: therefore more experience is needed. In the following evaluation we report the results of switching from iron gluconate (our previous standard therapy) to FCM in HD patients.
Primary Endpoint
switching effects on iron parameters (TSAT, ferritin) and hemoglobin.
Secondary Endpoints
switching effects on iron and ESA doses administered
Method
Study design: retrospective review of data from 106 HD patients from 2 Italian different dialysis centers, who were switched from iron gluconate to ferric carboxymaltose in a 1: 1 ratio.
Study duration: 9 months (3 months pre-switch, 6 months post-switch)
Treatment schedule: -ferritin <100 ng/ml and/or TSAT <20%: 100 mg of iron/weekly
-ferritin <200 μg/l, or TSAT<20%: 100 mg of iron/weekly
-ferritin 200–500 μg/l, and/or TSAT 20–30%: 100 mg of iron/every 2 weeks
-ferritin 500–800 μg/l and/or TSAT 30–50%: 100 mg of iron/monthly
-ferritin> 800 μg/l and/or TSAT>50%: no iron.
Hb, TSAT, Ferritin and PCR evaluation every 4 weeks.
Results
after switching from iron gluconate to FCM, Hb levels were stable or improved, reaching a significantly higher percentage of target patients (from 60% to 80% with Hb > 10,5 g/l). The switch was also associated with a significant improvement of iron status, unrelated to iron dose: the percentage of patients with a target TSAT (TSAT >=20%) has doubled after six months, moving from 30% to 70%, while the average consumption trend of FCM decreasing over time (-48% after six months). It was also shown a marked reduction in ESA consumption: the ESA dose was decreased on average by -1907 IU per patient/month.
Conclusion
The switch from iron gluconate to FCM is associated with a better control of iron status and iron anemia in CKD patients on hemodialysis. The treatment schedule proposed has guaranteed to reach the primary and secondary endpoints, underlining the importance and the effectiveness of a tailored therapeutic protocol.
Background Lecithin:cholesterol acyltransferase (LCAT) is responsible for cholesterol esterification in plasma. Mutations of LCAT gene cause familial LCAT deficiency, a metabolic disorder ...characterized by hypoalphalipoproteinemia. Apolipoprotein B (apoB) is the main protein component of very-low-density lipoproteins and low-density lipoprotein (LDL). Mutations of APOB gene cause familial hypobetalipoproteinemia, a codominant disorder characterized by low plasma levels of LDL cholesterol and apoB. Objective This was a genetic and biochemical analysis of an Italian kindred with hypobetalipoproteinemia whose proband presented with hypoalphalipoproteinemia and severe chronic kidney disease. Methods Plasma lipids and apolipoproteins, cholesterol esterification, and high-density lipoprotein (HDL) subclass distribution were analyzed. LCAT and APOB genes were sequenced. Results The proband had severe impairment of plasma cholesterol esterification and high preβ-HDL content. He was heterozygote for the novel LCAT P406L variant, as were two other family members. The proband’s wife and children presented with familial hypobetalipoproteinemia and were heterozygotes for the novel apoB H1401R variant. Cholesterol esterification rate of apoB H1401R carriers was reduced, likely attributable to the low amount of circulating LDL. After renal transplantation, proband’s lipid profile, HDL subclass distribution, and plasma cholesterol esterification were almost at normal levels, suggesting a mild contribution of the LCAT P406L variant to his pretransplantation severe hypoalphalipoproteinemia and impairment of plasma cholesterol esterification. Conclusion LCAT P406L variant had a mild effect on lipid profile, HDL subclass distribution, and plasma cholesterol esterification. ApoB H1401R variant was identified as possible cause of familial hypobetalipoproteinemia and resulted in a reduction of cholesterol esterification rate.
LCAT deficiency: a nephrological diagnosis Boscutti, Giuliano; Calabresi, Laura; Pizzolitto, Stefano ...
Giornale italiano di nefrologia,
2011 Jul-Aug, Letnik:
28, Številka:
4
Journal Article
Recenzirano
A genetic mendelian autosomal recessive condition of deficiency of lecithin- cholesterol acyltransferase (LCAT) can produce two different diseases: one highly interesting nephrologic picture of ...complete enzymatic deficiency (lecithin:cholesterol acyltransferase deficiency; OMIM ID #245900; FLD), characterized by the association of dyslipidemia, corneal opacities, anemia and progressive nephropathy; and a partial form (fish eye disease; OMIM ID #136120; FED) with dyslipidemia and progressive corneal opacities only. The diagnosis of FLD falls first of all under the competence of nephrologists, because end-stage renal disease appears to be its most severe outcome. The diagnostic suspicion is based on clinical signs (corneal opacities, more severe anemia than expected for the degree of chronic renal failure, progressive proteinuric nephropathy) combined with histology obtained by kidney biopsy (glomerulopathy evolving toward sclerosis with distinctive lipid deposition). However, the final diagnosis, starting with a finding of extremely low levels of HDL-cholesterol, requires collaboration with lipidology Centers that can perform sophisticated investigations unavailable in common laboratories. To be heterozygous for a mutation of the LCAT gene is one of the monogenic conditions underlying primary hypoalphalipoproteinemia (OMIM ID #604091). This disease, which is characterized by levels of HDL-cholesterol below the 5th percentile of those of the examined population (<28 mg/dL for Italians), has heritability estimates between 40% and 60% and is considered to be a predisposing condition for coronary artery disease. Nevertheless, some monogenic forms, and especially those associated with LCAT deficiency, seem to break the rule, confirming once more the value of a proper diagnosis before drawing prognostic conclusions from a laboratory marker. As in many other rare illnesses, trying to discover all the existing cases will contribute to allow studies broad enough to pave the way for further therapies, in this case also fostering the production by industries of the lacking enzyme by genetic engineering. Epidemiological studies, although done on selected populations such as hypoalphalipoproteinemia patients on dialysis and with the effective genetic tools of today, have been disappointing in elucidating the disease. Spreading the clinical knowledge of the disease and its diagnostic course among nephrologists seems to be the best choice, and this is the aim of our work.
This article investigates the form of European universities to determine the extent to which they resemble the characteristics of complete organizations and whether the forms are associated with ...modernization policy pressure, national institutional frames and organizational characteristics. An original data set of twenty-six universities from eight countries was used. Specialist universities have a stronger identity, whereas the level of hierarchy and rationality is clearly associated with the intensity of modernization policies. At the same time, evidence suggests limitations for universities to become complete, as mechanisms allowing the development of some dimensions seemingly constrain the capability to develop others.
In differentiated cells, aging is associated with hypermethylation of DNA regions enriched in repressive histone post-translational modifications. However, the chromatin marks associated with changes ...in DNA methylation in adult stem cells during lifetime are still largely unknown. Here, DNA methylation profiling of mesenchymal stem cells (MSCs) obtained from individuals aged 2 to 92 yr identified 18,735 hypermethylated and 45,407 hypomethylated CpG sites associated with aging. As in differentiated cells, hypermethylated sequences were enriched in chromatin repressive marks. Most importantly, hypomethylated CpG sites were strongly enriched in the active chromatin mark H3K4me1 in stem and differentiated cells, suggesting this is a cell type-independent chromatin signature of DNA hypomethylation during aging. Analysis of scedasticity showed that interindividual variability of DNA methylation increased during aging in MSCs and differentiated cells, providing a new avenue for the identification of DNA methylation changes over time. DNA methylation profiling of genetically identical individuals showed that both the tendency of DNA methylation changes and scedasticity depended on nongenetic as well as genetic factors. Our results indicate that the dynamics of DNA methylation during aging depend on a complex mixture of factors that include the DNA sequence, cell type, and chromatin context involved and that, depending on the locus, the changes can be modulated by genetic and/or external factors.
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