Search

Abstract Background IgA nephropathy (IgAN) or Berger's disease, is the most common glomerulonephritis in the world diagnosed in renal biopsied patients. The involvement of genetic factors in the pathogenesis of the IgAN is evidenced by ethnic and geographic variations in prevalence, familial clustering in isolated populations, familial aggregation and by the identification of a genetic linkage to locus IGAN1 mapped on 6q22–23. This study seems to imply a single major locus, but the hypothesis of multiple interacting loci or genetic heterogeneity cannot be ruled out. The organization of a multi-centre Biobank for the collection of biological samples and clinical data from IgAN patients and relatives is an important starting point for the identification of the disease susceptibility genes. Description The IgAN Consortium organized a Biobank, recruiting IgAN patients and relatives following a common protocol. A website was constructed to allow scientific information to be shared between partners and to divulge obtained data (URL: http://www.igan.net). The electronic database, the core of the website includes data concerning the subjects enrolled. A search page gives open access to the database and allows groups of patients to be selected according to their clinical characteristics. DNA samples of IgAN patients and relatives belonging to 72 multiplex extended pedigrees were collected. Moreover, 159 trios (sons/daughters affected and healthy parents), 1068 patients with biopsy-proven IgAN and 1040 healthy subjects were included in the IgAN Consortium Biobank. Some valuable and statistically productive genetic studies have been launched within the 5th Framework Programme 1998–2002 of the European project No. QLG1-2000-00464 and preliminary data have been published in "Technology Marketplace" website: http://www.cordis.lu/marketplace. Conclusion The first world IgAN Biobank with a readily accessible database has been constituted. The knowledge gained from the study of Mendelian diseases has shown that the genetic dissection of a complex trait is more powerful when combined linkage-based, association-based, and sequence-based approaches are performed. This Biobank continuously expanded contains a sample size of adequately matched IgAN patients and healthy subjects, extended multiplex pedigrees, parent-child trios, thus permitting the combined genetic approaches with collaborative studies.

Sudden cardiac death (SCD) represents a major cause of death in end-stage kidney disease (ESKD). The precise estimate of its incidence is difficult to establish because studies on the incidence of SCD in ESKD are often combined with those related to sudden cardiac arrest (SCA) occurring during a haemodialysis (HD) session. The aim of the European Dialysis Working Group of ERA-EDTA was to critically review the current literature examining the causes of extradialysis SCD and intradialysis SCA in ESKD patients and potential management strategies to reduce the incidence of such events. Extradialysis SCD and intradialysis SCA represent different clinical situations and should be kept distinct. Regarding the problem, numerically less relevant, of patients affected by intradialysis SCA, some modifiable risk factors have been identified, such as a low concentration of potassium and calcium in the dialysate, and some advantages linked to the presence of automated external defibrillators in dialysis units have been documented. The problem of extra-dialysis SCD is more complex. A reduced left ventricular ejection fraction associated with SCD is present only in a minority of cases occurring in HD patients. This is the proof that SCD occurring in ESKD has different characteristics compared with SCD occurring in patients with ischaemic heart disease and/or heart failure and not affected by ESKD. Recent evidence suggests that the fatal arrhythmia in this population may be due more frequently to bradyarrhythmias than to tachyarrhythmias. This fact may partly explain why several studies could not demonstrate an advantage of implantable cardioverter defibrillators in preventing SCD in ESKD patients. Electrolyte imbalances, frequently present in HD patients, could explain part of the arrhythmic phenomena, as suggested by the relationship between SCD and timing of the HD session. However, the high incidence of SCD in patients on peritoneal dialysis suggests that other risk factors due to cardiac comorbidities and uraemia per se may contribute to sudden mortality in ESKD patients., (© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Haemodialysis remains the most widely used treatment for patients with end-stage renal disease. Despite the progress that has occurred in the treatment of end-stage renal disease over the last six decades, there has been a failure to translate this into the desired clinical benefits, with morbidity and mortality rates among patients on haemodialysis remaining unacceptably high. Recently, however, there have been expectations that the significant advances that took place over the last few years may result in improved outcomes. New medications for the treatment of anaemia and secondary hyperparathyroidism, as well as novel trends in the areas of iron therapy, diabetes management and physical exercise are among the most important advances which, taken together, are changing the standards of care for patients on haemodialysis. The latest advances, of relevance not only to specialists in Renal Medicine but also to general practitioners caring for these patients, are reviewed in this collaborative paper.

COVID-19, a disease caused by a novel coronavirus, is a major global human threat that has turned into a pandemic. This novel coronavirus has specifically high morbidity in the elderly and in comorbid populations. Uraemic patients on dialysis combine an intrinsic fragility and a very frequent burden of comorbidities with a specific setting in which many patients are repeatedly treated in the same area (haemodialysis centres). Moreover, if infected, the intensity of dialysis requiring specialized resources and staff is further complicated by requirements for isolation, control and prevention, putting healthcare systems under exceptional additional strain. Therefore, all measures to slow if not to eradicate the pandemic and to control unmanageably high incidence rates must be taken very seriously. The aim of the present review of the European Dialysis (EUDIAL) Working Group of ERA-EDTA is to provide recommendations for the prevention, mitigation and containment in haemodialysis centres of the emerging COVID-19 pandemic. The management of patients on dialysis affected by COVID-19 must be carried out according to strict protocols to minimize the risk for other patients and personnel taking care of these patients. Measures of prevention, protection, screening, isolation and distribution have been shown to be efficient in similar settings. They are essential in the management of the pandemic and should be taken in the early stages of the disease., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Life-sustaining haemodialysis requires a durable vascular access (VA) to the circulatory system. The ideal permanent VA must provide longevity for use with minimal complication rate and supply sufficient blood flow to deliver the prescribed dialysis dosage. Arteriovenous fistulas (AVFs) have been endorsed by many professional societies as the VA of choice. However, the high prevalence of comorbidities, particularly diabetes mellitus, peripheral vascular disease and arterial hypertension in elderly people, usually make VA creation more difficult in the elderly. Many of these patients may have an insufficient vasculature for AVF maturation. Furthermore, many AVFs created prior to the initiation of haemodialysis may never be used due to the competing risk of death before dialysis is required. As such, an arteriovenous graft and, in some cases, a central venous catheter, become a valid alternative form of VA. Consequently, there are multiple decision points that require careful reflection before an AVF is placed in the elderly. The traditional metrics of access patency, failure and infection are now being seen in a broader context that includes procedure burden, quality of life, patient preferences, morbidity, mortality and cost. This article of the European Dialysis (EUDIAL) Working Group of ERA-EDTA critically reviews the current evidence on VA in elderly haemodialysis patients and concludes that a pragmatic patient-centred approach is mandatory, thus considering the possibility that the AVF first approach should not be an absolute., (© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Immunoglobulin A nephropathy (IgAN) is a complex multifactorial disease characterized by genetic factors that influence the pathogenesis of the disease. In this context, an intriguing role could be ascribed to copy number variants (CNVs). We performed the whole-genome screening of CNVs in familial IgAN patients, their healthy relatives and healthy subjects (HSs). In the initial screening, we included 217 individuals consisting of 51 biopsy-proven familial IgAN cases and 166 healthy relatives. We identified 148 IgAN-specific aberrations, specifically 105 loss and 43 gain, using a new statistical approach that allowed us to identify aberrations that were concordant across multiple samples. Several CNVs overlapped with regions evidenced by previous genome-wide genetic studies. We focused our attention on a CNV located in chromosome 3, which contains the TLR9 gene and found that IgAN patients characterized by deteriorated renal function carried low copy number of this CNV. Moreover, the TLR9 gene expression was low and significantly correlated with the loss aberration. Conversely, IgAN patients with normal renal function had no aberration and the TLR9 mRNA was expressed at the same level as in HSs. We confirmed our data in another cohort of Greek subjects. In conclusion, here we performed the first genome-wide CNV study in IgAN identifying structural variants that could help the genetic dissection of this complex disease, and pointed out a loss aberration in the chromosome 3, which is responsible for the downregulation of TLR9 expression that, in turn, could contribute to the deterioration of the renal function in IgAN patients.

Atherosclerosis is a chronic inflammatory process accounting for increased cardiovascular and cerebrovascular morbidity and mortality. A wealth of recent data has implicated several infectious agents, mainly Chlamydophila pneumoniae, Helicobacter pylori, CMV and periodontal pathogens, in atherosclerosis. Thus, we sought to comprehensively review the available data on the topic, exploring in particular the pathogenetic mechanisms, and discuss anticipated future directions.

Background: In the present prospective, controlled, observational cohort study, we investigated the effects of the use of a vitamin E-coated membrane dialyser (VEM) on markers of chronic inflammation, oxidative stress and endothelial cell apoptosis in end-stage renal disease (ESRD) patients on chronic haemodialysis (HD), as long as evidence of their effects on these pathogenetic routes are inconclusive as yet, despite their use for the last several years., Methods: Thirty-five stable ESRD patients underwent HD with the use of VEM for 6 months. Another 25 age- and sex-matched ESRD patients, being dialysed with conventional dialysers, served as controls. In both patient groups, beyond complete haematology and biochemistry work-up, serum CRP, apolipoproteins A1 and B, lipoprotein (a) (Lp(a)), hsIL-6, MCP-1, sICAM-1, sVCAM-1, sE-selectin, sFas and sFasL as well as plasma oxLDL, TBARS and TAS levels were determined at baseline and at 6 months of the study., Results: In the VEM group at 6 months, a significant reduction in CRP (P = 0.004), IL-6 (P = 0.004) and sICAM-1 (P = 0.04) levels was observed compared with baseline, along with a remarkable change in all markers of oxidative stress, i.e. increase in TAS (P = 0.005) and decrease in TBARS (P = 0.04) and oxLDL (P < 0.001). No significant changes were noted in the other parameters studied in the VEM group or in any parameter studied in the controls. Between the groups, significant differences were found in the change of CRP (P = 0.001), sICAM-1 (P = 0.03) and oxLDL (P = 0.04) compared with baseline., Conclusions: HD with the use of VEM resulted in a significant reduction in inflammation and oxidative stress markers. Larger prospective randomized studies will need to confirm the findings of the present observational study.

Aim: We investigated the effects of simvastatin on markers of inflammation, oxidative stress and endothelial cell apoptosis in hyperlipidemic endstage renal disease patients on chronic hemodialysis (HD)., Methods: In 25 hyperlipidemic HD patients who received 10 mg of simvastatin for 6 months and another 25 controls, the extended lipid profile and serum hsIL-6, MCP-1, sICAM-1, sVCAM-1, and sE-selectin, plasma oxLDL, and serum sFas and sFasL levels were determined at baseline, 3 months and 6 months. In 18 patients of the simvastatin group, the expression of CD14, CD16, CD62L and CD64 on monocyfes was determined with flow cytometry., Result: Simvastatin treatment resulted in significant reductions in serum lipid levels at 3 months and beyond, compared to at baseline. Moreover, at 6 months, simvastatin caused a significant reduction in CRP (p < 0.001), which correlated to the decrease in total and LDL cholesterol levels, as well as a significant reduction in IL-6 (p=0.001), sICAM-1 (p < 0.001), sVCAM-1 (p < 0.001), oxLDL (p=0.001), sFas (p=0.02) and CD14 expression (p < 0.001), compared to baseline values. No significant changes in the controls were noticed during the study., Conclusion: In conclusion, in hyperlipidemic HD patients, simvastatin treatment resulted in a significant reduction in markers of endothelial dysfunction, inflammation, oxidative stress, endothelial cell apoptosis and peripheral blood monocyte stimulation. The reduction in CRP appears to be related to the lipid-lowering effects of simvastatin.

Atomic force microscope (AFM) has been used incrementally over the last decade in cell biology. Beyond its usefulness in high resolution imaging, AFM also has unique capabilities for probing the viscoelastic properties of living cells in culture and, even more, mapping the spatial distribution of cell mechanical properties, providing thus an indirect indicator of the structure and function of the underlying cytoskeleton and cell organelles. AFM measurements have boosted our understanding of cell mechanics in normal and diseased states and provide future potential in the study of disease pathophysiology and in the establishment of novel diagnostic and treatment options.

Statins (3-hydroxy-3-methyl glutaryl coenzyme A [HMG-CoA] reductase inhibitors) are the most commonly used lipid-lowering drugs. Their main lipid-lowering effect is achieved by an increase in the expression of low-density lipoprotein cholesterol receptors associated with inhibition of cholesterol synthesis through inhibition of HMG-CoA reductase - the first and rate-limiting step in cholesterol synthesis. However, beyond cholesterol synthesis inhibition, inhibition of the HMG-CoA reductase affects as well the synthesis of other molecules with significant roles in different, yet often intercalating, metabolic pathways. On this basis, and supported by an increasing series of advocating epidemiological and experimental data, an extended dialogue has been established over the last few years regarding the nonlipid or "pleiotropic" actions of statins.

Background: IgA nephropathy (IgAN) is a common form of primary glomerulonephritis characterized by diffuse glomerular mesangial IgA1 deposition that leads to mesangial proliferation and chronic glomerular inflammation. Analyses of serum IgA1 from IgAN patients revealed an abnormal galactosylation of the O-linked carbohydrate moieties of IgA that may be a result of altered activity of core 1 beta1,3-galactosyltransferase (C1GalT1). To evaluate the association between C1GalT1 single nucleotide polymorphisms (SNPs) and IgAN, we performed a case control study on cohorts from the Italian population., Methods: We sequenced C1GalT1 coding and promoter regions in 284 IgAN patients and 210 healthy controls. The functional role of 3' untranslated region (3'UTR) SNPs was studied using electrophoretic mobility shift assays and real-time quantitative PCR., Results: We analyzed 8 SNPs in the C1GalT1 gene: 5 SNPs were in the promoter region and 3 SNPs in the 3'UTR. The allele 1365G in the 3'UTR was significantly more frequent in IgAN patients than in healthy controls., Conclusion: The 1365G allele and 1365G/G genotype seem to confer susceptibility to IgAN.

We designed the present case-control study in order to examine the validity of apolipoprotein (apo) A-I, B, apoB/apoA-I ratio and Lp(a) as alternative markers of cardiovascular morbidity in end-stage renal disease (ESRD) patients undergoing chronic hemodialysis (HD). Twenty-five HD patients (18 males, mean age 63, range 52-69 years) comprised the group with prevalent cardiovascular disease (CVD) and 50 HD patients (35 males, mean age 62, range 40-77 years) with non evident cardiovascular disease history constituted the second study group. Patients with CVD had significantly higher concentrations of serum apoB, apoB/apoA-I ratio and Lp(a), and lower levels of apoA-I compared to patients without incident CVD. All three parameters studied were correlated with cardiovascular morbidity, i.e. apoA-I negatively and apoB and apoB/apoA-I ratio positively (r = -0.6, P < 0.05; r = 0.659, P < 0.01; and r = 0.614, P < 0.01, respectively). Furthermore, logCRP exhibited as well a significant positive correlation with cardiovascular morbidity (r = 0.704, P < 0.001), not this being the case for Lp(a) which was not found to exhibit such a correlation (r = 0.05, P = NS). Among them, apoB and apoB/apoA-I ratio exhibited the characteristics most coherent to CVD. The age- and sex-adjusted OR for the presence of CVD was 2.3 and 2.0, respectively, which remained independent of any confounding effect of inflammation. In conclusion, serum apoB levels and apoB/apoA-I ratio exhibit characteristics of credible independent markers of in HD patients.

T helper (h) lymphocytes in pathogenic immune response at mucosal effector site play a key role in IgA nephropathy (IgAN). We evaluated the impact of some Th1/Th2/Th3/T(R)-type, and of monocyte/macrophage cytokines on IgAN susceptibility with a family-based association study including 53 patients, 45 complete trios, 4 incomplete trios and 36 discordant siblings. Cytokine gene polymorphisms with a potential regulatory role on their production were investigated using the family-based association test (FBAT): IFNgamma intron-1 CA repeat at position 1349-1373; IL-13 -1055C/T; TGFbeta +915G/C; IL-10 5'-proximal and distal microsatellites; TNFalpha -308G/A, -238G/A. The FBAT multi-allelic analysis showed an association between IFNgamma polymorphism and susceptibility to IgAN (P=0.03). The bi-allelic analysis evidenced that the 13-CA repeat allele was preferentially transmitted to the affected individuals (P=0.006; Bonferroni P-value=0.04). The direct sequencing of IFNgamma amplicons showed a strict association between the 13-CA repeat allele and the A variant of the +874T/A single nucleotide polymorphism (SNP rs2430561) directly adjacent to the 5' end of the microsatellite. The in vitro production of IFNgamma evaluated in peripheral blood mononuclear cells from 10 genotyped patients demonstrated a correlation between the +874A allele and a lower production of IFNgamma (P=0.028 Mann-Whitney test). This SNP affects IFNgamma production lying within a binding site for the transcription factor NF-kappaB. No significant difference was observed in the 15 years renal survival between IgAN patients carrying different IFNgamma gene polymorphisms. This first family-based association study demonstrates that the +874A allele, strictly associated with IFNgamma 13-CA repeat allele, confers susceptibility to IgAN, without influencing renal survival.

Background: Among the non-classic cardiovascular disease risk factors in end-stage renal disease patients on chronic hemodialysis (HD), plasma fibrinogen, D-dimer, and von Willebrand factor (vWf) levels are potential markers of cardiovascular morbidity. We designed this case-control study to investigate their validity and any differences between them., Material/methods: Twenty-five HD patients (18 males, mean age: 63, range: 52-69 years) comprised the group with prevalent cardiovascular disease (CVD) and 50 HD patients (35 males, mean age: 62, range: 40-77 years) with non-evident cardiovascular disease history constituted the second study group. Twenty-five healthy non-smoking volunteers served as controls for comparison with the study groups., Results: Patients with CVD had significantly higher concentrations of plasma fibrinogen, D-dimer, and vWf than patients without incident CVD. All three parameters correlated positively with cardiovascular morbidity, i.e. fibrinogen (r=0.378, P<0.001), logDD (r=0.70, P<0.001), vWf (r=0.214, P<0.001), and logCRP (r=0.704, P<0.001). Among them, D-dimer exhibited the characteristics most coherent with CVD. The age- and sex-adjusted odds ratio (OR) of D-dimer for the presence of CVD was 2.0, which did not change appreciably when adjustments for several pathophysiological clusters of variables were made, except for a marginal reduction in OR following adjustment for markers of inflammation., Conclusions: Among the coagulation molecules studied, plasma D-dimer levels exhibited the characteristics most coherent with associated CVD and were found to be strongly and independently associated with the prevalence of CVD in HD patients.

Background: Recently emerging evidence suggests that endothelial adhesion molecules may participate in atherogenesis. The aim of the present report was to investigate the probable association of circulating ICAM-1, VCAM-1 and E-selectin with atherosclerotic disease in chronic haemodialysis (HD) patients., Methods: One hundred and twelve HD patients and 50 age- and sex-matched healthy normotensive controls participated in the study. Atherosclerotic disease in both groups was assessed by measuring intima-media thickness (IMT) and plaque score of the common carotid arteries using an ultrasound scanner. In addition, in a follow-up study, the survival of 81 patients after a mean period of 26 months was analysed in relation to ICAM-1 and VCAM-1 levels., Results: IMT and plaque score were significantly higher in HD patients compared with control subjects (P < 0.001 and P < 0.0001, respectively). The above ultrasonographic indices were correlated with age both in controls (P = 0.0001 and P = 0.002, respectively) and HD patients (P = 0.0001 and P = 0.0001, respectively). A significant relationship was observed between IMT and systolic blood pressure (BP) both in controls and in HD patients (P = 0.002 and P = 0.01, respectively). In HD patients, plaque score was also correlated with systolic BP (P = 0.02). In HD patients, IMT and plaque score were correlated significantly with log CRP values (P = 0.01 and P = 0.01, respectively). Multivariate analysis showed that log CRP values were a strong independent contributor to plaque score (P = 0.01). IMT was significantly correlated with ICAM-1 and VCAM-1 concentrations (P = 0.0001 and P = 0.003, respectively). Multivariate analysis showed that ICAM-1 concentrations were a strong independent correlate of IMT (P = 0.001). E-selectin concentrations did not show any relation with IMT or plaque score. During the follow-up period, 13 of the 81 patients died. Survival analyses showed that patients with increased ICAM-1 had a shorter survival than patients with normal ICAM-1 values and that serum ICAM-1 levels were a strong predictor of death., Conclusions: In HD patients, carotid atherosclerosis is associated with inflammation and circulating levels of soluble adhesion molecules ICAM-1 and VCAM-1. The correlations between serum ICAM-1 and IMT and ICAM-1 and survival may indicate that this molecule could be a marker of a process that contributes to the high mortality of HD patients.