Hypermethylation-Mediated Silencing of CIDEA, MAL and PCDH17 Tumour Suppressor Genes in Canine DLBCL: From Multi-Omics Analyses to Mechanistic Studies.

Gene expression is controlled by epigenetic deregulation, a hallmark of cancer. The DNA methylome of canine diffuse large B-cell lymphoma (cDLBCL), the most frequent malignancy of B-lymphocytes in dog, has recently been investigated, suggesting that aberrant hypermethylation of CpG loci is associated with gene silencing. Here, we used a multi-omics approach (DNA methylome, transcriptome and copy number variations) combined with functional in vitro assays, to identify putative tumour suppressor genes subjected to DNA methylation in cDLBCL. Using four cDLBCL primary cell cultures and CLBL-1 cells, we found that CiDEA, MAL and PCDH17, which were significantly suppressed in DLBCL samples, were hypermethylated and also responsive (at the DNA, mRNA and protein level) to pharmacological unmasking with hypomethylating drugs and histone deacetylase inhibitors. The regulatory mechanism underneath the methylation-dependent inhibition of those target genes expression was then investigated through luciferase and in vitro methylation assays. In the most responsive CpG-rich regions, an in silico analysis allowed the prediction of putative transcription factor binding sites influenced by DNA methylation. Interestingly, regulatory elements for AP2, MZF1, NF-kB, PAX5 and SP1 were commonly identified in all three genes. This study provides a foundation for characterisation and experimental validation of novel epigenetically-dysregulated pathways in cDLBCL.

Development and Validation of the Acute PNeumonia Early Assessment Score for Safely Discharging Low-Risk SARS-CoV-2-Infected Patients from the Emergency Department.

A continuous demand for assistance and an overcrowded emergency department (ED) require early and safe discharge of low-risk severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients. We developed (n = 128) and validated (n = 330) the acute PNeumonia early assessment (aPNea) score in a tertiary hospital and preliminarily tested the score on an external secondary hospital (n = 97). The score's performance was compared to that of the National Early Warning Score 2 (NEWS2). The composite outcome of either death or oral intubation within 30 days from admission occurred in 101 and 28 patients in the two hospitals, respectively. The area under the receiver operating characteristic (AUROC) curve of the aPNea model was 0.86 (95% confidence interval (CI), 0.78-0.93) and 0.79 (95% CI, 0.73-0.89) for the development and validation cohorts, respectively. The aPNea score discriminated low-risk patients better than NEWS2 at a 10% outcome probability, corresponding to five cut-off points and one cut-off point, respectively. aPNea's cut-off reduced the number of unnecessary hospitalizations without missing outcomes by 27% (95% CI, 9-41) in the validation cohort. NEWS2 was not significant. In the external cohort, aPNea's cut-off had 93% sensitivity (95% CI, 83-102) and a 94% negative predictive value (95% CI, 87-102). In conclusion, the aPNea score appears to be appropriate for discharging low-risk SARS-CoV-2-infected patients from the ED.

G-Quadruplex Modulation of SP1 Functional Binding Sites at the KIT Proximal Promoter.

The regulation of conformational arrangements of gene promoters is a physiological mechanism that has been associated with the fine control of gene expression. Indeed, it can drive the time and the location for the selective recruitment of proteins of the transcriptional machinery. Here, we address this issue at the KIT proximal promoter where three G-quadruplex forming sites are present (kit1, kit2 and kit*). On this model, we focused on the interplay between G-quadruplex (G4) formation and SP1 recruitment. By site directed mutagenesis, we prepared a library of plasmids containing mutated sequences of the WT KIT promoter that systematically exploited different G4 formation attitudes and SP1 binding properties. Our transfection data showed that the three different G4 sites of the KIT promoter impact on SP1 binding and protein expression at different levels. Notably, kit2 and kit* structural features represent an on-off system for KIT expression through the recruitment of transcription factors. The use of two G4 binders further helps to address kit2-kit* as a reliable target for pharmacological intervention.

DNA elements for constitutive androstane receptor- and pregnane X receptor-mediated regulation of bovine CYP3A28 gene.

The regulation of cytochrome P450 3A (CYP3A) enzymes is established in humans, but molecular mechanisms of its basal and xenobiotic-mediated regulation in cattle are still unknown. Here, ~10 kbp of the bovine CYP3A28 gene promoter were cloned and sequenced, and putative transcription factor binding sites were predicted. The CYP3A28 proximal promoter (PP; -284/+71 bp) contained DNA elements conserved among species. Co-transfection of bovine nuclear receptors (NRs) pregnane X and constitutive androstane receptor (bPXR and bCAR) with various CYP3A28 promoter constructs into hepatoma cell lines identified two main regions, the PP and the distal fragment F3 (-6899/-4937 bp), that were responsive to bPXR (both) and bCAR (F3 fragment only). Site-directed mutagenesis and deletion of NR motif ER6, hepatocyte nuclear factor 1 (HNF-1) and HNF-4 binding sites in the PP suggested either the involvement of ER6 element in bPXR-mediated activation or the cooperation between bPXR and liver-enriched transcription factors (LETFs) in PP transactivation. A putative DR5 element within the F3 fragment was involved in bCAR-mediated PP+F3 transactivation. Although DNA enrichment by anti-human NR antibodies was quite low, ChIP investigations in control and RU486-treated BFH12 cells, suggested that retinoid X receptor α (RXRα) bound to ER6 and DR5 motifs and its recruitment was enhanced by RU486 treatment. The DR5 element seemed to be recognized mainly by bCAR, while no clear-cut results were obtained for bPXR. Present results point to species-differences in CYP3A regulation and the complexity of bovine CYP3A28 regulatory elements, but further confirmatory studies are needed.

Epidemiology of amyotrophic lateral sclerosis in Friuli-Venezia Giulia, North-Eastern Italy, 2002-2014: a retrospective population-based study.

OBJECTIVES: To describe the epidemiology of Amyotrophic Lateral Sclerosis (ALS) in Friuli-Venezia Giulia (FVG) region, Italy, over a 13-year period (2002-2014), estimating ALS (a) incidence, prevalence, and clinical features; (b) mortality, also comparing Udine municipality to the rest of FVG. METHODS: We conducted a retrospective population-based study. ALS incident cases were ascertained using multiple sources and validated through expert review. We calculated crude and standardized incidence rate (IR), point prevalence and mortality rate (MR), each with 95% confidence interval. Standardized incidence (SIR) and mortality (SMR) ratio were calculated to compare Udine to FVG. RESULTS: Among 444 incident cases (50.0% men, median age 68.5 years), onset was bulbar in 30.2%, spinal in 59.9%, mixed in 9.9%; 3.6% had familial ALS. Crude and 2000 European population standardized IR was respectively 2.81 (2.56-3.09) and 2.09 (1.89-2.29) per 100,000 person-years. Standardized male-to-female incidence ratio was 1.05. IR peaked at age 65-74 years (men: 9.93, 8.04-12.32; women: 7.74, 6.18-9.67) and decreased thereafter. Prevalence was 8.36 (6.74-9.97) cases per 100,000 inhabitants on 30 June 2009 and 7.98 (6.40-9.56) on 30 June 2014. SIR was 1.20 and SMR 1.11. CONCLUSIONS: When assessed over a long period, incidence of ALS was in the range of Italian and European population-based registries and showed a consistent pattern by age and sex. IR and MR were only slightly higher in Udine vs. FVG.

Validation of epigenetic mechanisms regulating gene expression in canine B-cell lymphoma: An in vitro and in vivo approach.

Despite canine B-cell Lymphoma (BCL) representing the most common haematological tumour, epigenetic events driving development and progression are scarcely known. Recently, canine Diffuse Large BCL (DLBCL) DNA methylome by genome-wide CpG microarray has identified genes and pathways associated to pathogenesis. To validate data previously obtained by array analysis, the CLBL-1 cell line was used and the HOXD10, FGFR2, ITIH5 and RASAL3 genes were selected. CLBL-1 cells were treated with two hypomethylating drugs (HDs; IC50, 50% inhibitory concentration), i.e. azacytidine and decitabine (DEC), either alone or in combination with three histone deacetylase inhibitors (HDACis; IC20), i.e. valproic acid, trichostatin and vorinostat. Following the incubation with both HDs, an overall decrease of promoter methylation was highlighted, thus confirming target genes hypermethylation. The highest mRNA restoration was observed following the exposure to HDs combined with HDACis, and mostly with valproic acid. Contrasting results were only obtained for RASAL3. An in vivo confirmation was finally attempted treating Nod-Scid mice engrafted with CLBL-1 cells with DEC. Although DEC did not arrest tumour growth, target genes promoter methylation was significantly reduced in DEC-treated mice vs controls. Overall, this work demonstrates that CLBL-1 cell line represents a reliable in vitro model to validate the methylation-dependent silencing of key genes for BCL; moreover, it may be useful for xenograft models in mice, despite its aggressive behaviour. In future, functional studies will be performed to deepen the role of selected genes on BCL pathogenesis and progression, and their methylation-dependent mechanism of regulation.

Targeting Canine KIT Promoter by Candidate DNA G-Quadruplex Ligands.

G-quadruplexes (G4) are nucleic acid secondary structures frequently assumed by G-rich sequences located mostly at telomeres and proto-oncogenes promoters. Recently, we identified, in canine KIT (v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog) promoter, two G-rich sequences able to fold into G4: d_kit1 and d_kit2_A16. In this study, an anthraquinone (AQ1) and an anthracene derivative (AN6), known to stabilize the G4 structures of the corresponding human h_kit1 and h_kit2, were tested on the canine G4 and in two canine mast cell tumor (MCT) cell lines (C2 and NI-1) to verify their capability to down-regulate KIT expression. The cytotoxicity of AQ1 and AN6 was determined using the Alamar Blue test; also the constitutive expression of KIT and other proto-oncogenes containing G4 structures in their promoter (BCL2, VEGFα, VEGFR2, KRAS, and TERT) was assessed by quantitative real-time polymerase chain reaction (qRT-PCR). Then the time- and dose-dependent effects of both ligands on target gene expression were assessed by qRT-PCR. All target genes were constitutively expressed up to 96 hours of culture. Both ligands decreased KIT mRNA levels and c-kit protein amount, and AN6 was comparatively fairly more effective. DNA interaction studies and a dual-luciferase gene reporter assay performed on a noncancerous canine cell line (Madin-Darby Canine Kidney cells) proved that this down-regulation was the result of the interaction of AN6 with KIT proximal promoter. Interestingly, our results only partially overlap with those previously obtained in human cell lines, where AQ1 was found as the most effective compound. These preliminary data might suggest AN6 as a promising candidate for the selective targeting of canine KIT-dependent tumors.

In Silico Identification of Piperidinyl-amine Derivatives as Novel Dual Binders of Oncogene c-myc/c-Kit G-quadruplexes.

In the last years, it has been shown that the DNA secondary structure known as G-quadruplex is also involved in the regulation of oncogenes transcription, such as c-myc, c-Kit, KRAS, Bcl-2, VEGF, and PDGF. DNA G-quadruplexes, formed in the promoter region of these proto-oncogenes, are considered alternative anticancer targets since their stabilization causes a reduction of the related oncoprotein overexpression. In this study, a structure-based virtual screening toward the experimental DNA G-quadruplex structures of c-myc and c-Kit was performed by using Glide for the docking analysis of a commercial library of approximately 693 000 compounds. The best hits were submitted to thermodynamic and biophysical studies, highlighting the effective stabilization of both G-quadruplex oncogene promoter structures for three N-(4-piperidinylmethyl)amine derivatives, thus proposed as a new class of dual G-quadruplex binders.

Mortality in Elderly Waiting-List Patients Versus Age-Matched Kidney Transplant Recipients: Where is the Risk?

The number of elderly patients on the waiting list (WL) for kidney transplantation (KT) has risen significantly in recent years. Because KT offers a better survival than dialysis therapy, even in the elderly, candidates for KT should be selected carefully, particularly in older waitlisted patients. Identification of risk factors for death in WL patients and prediction of both perioperative risk and long-term post-transplant mortality are crucial for the proper allocation of organs and the clinical management of these patients in order to decrease mortality, both while on the WL and after KT. In this review, we examine the clinical results in studies concerning: a) risk factors for mortality in WL patients and KT recipients; 2) the benefits and risks of performing KT in the elderly, comparing survival between patients on the WL and KT recipients; and 3) clinical tools that should be used to assess the perioperative risk of mortality and predict long-term post-transplant survival. The acknowledgment of these concerns could contribute to better management of high-risk patients and prophylactic interventions to prolong survival in this particular population, provided a higher mortality is assumed.

DNA methylation profiling reveals common signatures of tumorigenesis and defines epigenetic prognostic subtypes of canine Diffuse Large B-cell Lymphoma.

Epigenetic deregulation is a hallmark of cancer characterized by frequent acquisition of new DNA methylation in CpG islands. To gain insight into the methylation changes of canine DLBCL, we investigated the DNA methylome in primary DLBCLs in comparison with control lymph nodes by genome-wide CpG microarray. We identified 1,194 target loci showing different methylation levels in tumors compared with controls. The hypermethylated CpG loci included promoter, 5'-UTRs, upstream and exonic regions. Interestingly, targets of polycomb repressive complex in stem cells were mostly affected suggesting that DLBCL shares a stem cell-like epigenetic pattern. Functional analysis highlighted biological processes strongly related to embryonic development, tissue morphogenesis and cellular differentiation, including HOX, BMP and WNT. In addition, the analysis of epigenetic patterns and genome-wide methylation variability identified cDLBCL subgroups. Some of these epigenetic subtypes showed a concordance with the clinical outcome supporting the hypothesis that the accumulation of aberrant epigenetic changes results in a more aggressive behavior of the tumor. Collectively, our results suggest an important role of DNA methylation in DLBCL where aberrancies in transcription factors were frequently observed, suggesting an involvement during tumorigenesis. These findings warrant further investigation to improve cDLBCL prognostic classification and provide new insights on tumor aggressiveness.

Indenocinnoline derivatives as G-quadruplex binders, topoisomerase IIα inhibitors and antiproliferative agents.

DNA intercalating agents are a consolidated therapeutic option in the treatment of tumor diseases. Starting from previous findings in the antiproliferative efficacy of a series of indeno[1,2-c]cinnoline-11-one derivatives, we performed a suitable decoration of this scaffold by means of a simple and straightforward chemistry, aiming to a) enlarge the planar core to a pentacyclic benzo[h]indeno[1,2-c]cinnoline-13-one and b) introduce a basic head tethered through a simple polymethylene chain. In fluorescence melting and fluorescence intercalator displacement assays, these new compounds displayed fair to very good intercalating properties on different nucleic acid strands, with preference for G-quadruplex sequences. Inhibition of human topoisomerase IIα and antiproliferative assays on HeLa and MCF7 tumor cell lines outlined a multitarget antiproliferative profile for tetracyclic 6 and pentacyclic derivative 20, both bearing a N,N-dimethylamine as the protonatable moiety. Particularly, compound 6 displayed a very potent inhibition of tumor cell proliferation, while 20 returned the highest thermal stabilization in melting experiments. In summary, these results outlined a potential of such highly planar scaffolds for nucleic acid binding and antiproliferative effects.

Screening of candidate G-quadruplex ligands for the human c-KIT promotorial region and their effects in multiple in-vitro models.

Stabilization of G-quadruplex (G4) structures in promoters is a novel promising strategy to regulate gene expression at transcriptional and translational levels. c-KIT proto-oncogene encodes for a tyrosine kinase receptor. It is involved in several physiological processes, but it is also dysregulated in many diseases, including cancer. Two G-rich sequences able to fold into G4, have been identified in c-KIT proximal promoter, thus representing suitable targets for anticancer intervention. Herein, we screened an "in house" library of compounds for the recognition of these G4 elements and we identified three promising ligands. Their G4-binding properties were analyzed and related to their antiproliferative, transcriptional and post-transcriptional effects in MCF7 and HGC27 cell lines. Besides c-KIT, the transcriptional analysis covered a panel of oncogenes known to possess G4 in their promoters.From these studies, an anthraquinone derivative (AQ1) was found to efficiently downregulate c-KIT mRNA and protein in both cell lines. The targeted activity of AQ1 was confirmed using c-KIT-dependent cell lines that present either c-KIT mutations or promoter engineered (i.e., α155, HMC1.2 and ROSA cells).Present results indicate AQ1 as a promising compound for the target therapy of c-KIT-dependent tumors, worth of further and in depth molecular investigations.

Peritoneal resting with heparinized lavage reverses peritoneal type I membrane failure. A comparative study of the resting effects on normal membranes.

BACKGROUND: Ultrafiltration failure (UFF) is a serious complication of long-term peritoneal dialysis (PD). Peritoneal rest (PR) has been demonstrated as a valid treatment to reverse the functional changes that occur in UFF. The effects of PR on a normally functioning human peritoneum are unknown but are expected to be neutral. Our hypothesis was that PR positively modifies peritoneal function in patients with UFF, in contrast to the absence of effects when PR is applied under normal conditions. PATIENTS AND METHODS: We studied 84 PR periods, comparing 35 patients with UFF and 49 controls (resting for abdominal surgery with temporary discontinuation of PD). We analyzed peritoneal transport pre-PR and post-PR by calculating the mass transfer coefficients of creatinine (Cr-MTAC), the dialysate/plasma creatinine ratio (D/P Cr) and the ultrafiltration (UF). RESULTS: Baseline data was similar for the 2 groups, although the UFF group had a longer median time in PD (39 [18 - 60] vs 10 [5 - 23] months; p = 0.00001). Peritoneal rest induced a decrease in D/P Cr, Cr-MTAC and an increase in UF capacity in the UFF group (p = 0.0001, p = 0.004 and p = 0.001, respectively), without causing changes in the control group. Peritoneal rest in patients with more than 6 months of UFF was not able to reduce peritoneal solute transport or improve UF capacity. Response to PR did not differ among UFF patients with or without a previous history of peritonitis. Peritoneal rest enabled patients with UFF to continue on PD for a median time of 23 months (range, 13 - 46 months). CONCLUSIONS: Peritoneal rest induces functional changes in patients with UFF but not in those with no functional abnormalities. This demonstrates that PR works only when abnormal but reversible functional conditions are present. However, the effect is highly dependent on how early PR is applied.

Sequencing and G-quadruplex folding of the canine proto-oncogene KIT promoter region: might dog be used as a model for human disease?

Downregulation of gene expression by induction of non-canonical DNA structures at promotorial level is a novel attractive anticancer strategy. In human, two guanine-rich sequences (h_kit1 and h_kit2) were identified in the promotorial region of oncogene KIT. Their stabilization into G-quadruplex structures can find applications in the treatment of leukemias, mastocytosis, gastrointestinal stromal tumor, and lung carcinomas which are often associated to c-kit mis-regulation. Also the most common skin cancer in domestic dog, mast cell tumor, is linked to a mutation and/or to an over-expression of c-kit, thus supporting dog as an excellent animal model. In order to assess if the G-quadruplex mediated mechanism of regulation of c-kit expression is conserved among the two species, herein we cloned and sequenced the canine KIT promoter region and we compared it with the human one in terms of sequence and conformational equilibria in physiologically relevant conditions. Our results evidenced a general conserved promotorial sequence between the two species. As experimentally confirmed, this grants that the conformational features of the canine kit1 sequence are substantially shared with the human one. Conversely, two isoforms of the kit2 sequences were identified in the analyzed dog population. In comparison with the human counterpart, both of them showed an altered distribution among several folded conformations.

Pretransplant peritoneal dialysis relative to hemodialysis improves long-term survival of kidney transplant patients: a single-center observational study.

BACKGROUND: Kidney transplantation is the best option for the treatment of end-stage renal disease in terms of survival and quality of life. These results can be influenced by the pretransplant dialysis modality. The aim of this study was to evaluate whether the pretransplantation dialysis modality influences patient and allograft survival beyond 10 years and examine the potential risk factors associated with the outcomes. METHODS: We conducted an observational, retrospective, single-center clinical study that included 236 patients [118 undergoing peritoneal dialysis (PD) and 118 undergoing hemodialysis (HD)] who proceeded to transplantation during the period December 1990-2002. Donor and recipient data were collected from our hospital's clinical registries. The follow-up period extended to the patient's death, the loss of the allograft, or loss to follow-up. The end date of the study was set at March 2012. RESULTS: In the multivariate analysis, the long-term patient survival rate was higher for the PD group than for the HD group [HR = 2.62 (1.01-6.8); p = 0.04]; however, the allograft survival rate was not significantly different between the two groups [HR = 0.68 (0.41-1.10); p = 0.12]. CONCLUSION: Pretransplantation dialysis modality is associated with long-term patient survival, with outcomes favoring peritoneal dialysis over hemodialysis. However, the pretransplant dialysis modality does not influence long-term graft loss risk.

Increased risk of fatal infections in women starting peritoneal dialysis.

BACKGROUND AND OBJECTIVES: Although cardiovascular disease (CVD) is an important cause of morbidity and mortality in patients with end-stage renal disease, non-CVD causes account for more than 50% of total deaths. We previously showed that, compared with men, women starting dialysis-- both hemodialysis and peritoneal dialysis (PD)--have higher non-CVD mortality rates. Here, we evaluate sex-specific outcomes in a large cohort of incident PD patients. METHODS: Incident de novo PD patients from the Andalusian SICATA Registry for 1999 - 2010, with follow-up until 31 December 2010 or up to 5 years, were investigated for fatal outcomes. Causes of death were extracted from medical records. The analysis used traditional and competing-risk Cox models for all-cause and cause-specific mortality in men and women, correcting in the competing-risk models for the events of kidney transplantation and transfer to hemodialysis. RESULTS: A total of 1458 patients (57% men; mean overall age: 55.3 ± 17.0 years) initiated PD in Andalusia during the study period. During follow-up, 350 deaths, 355 renal transplantation procedures, and 331 transfers to hemodialysis were recorded. Vascular disease and diabetic nephropathy were the most frequent causes of kidney failure in men; other causes were more common in women. In the traditional Cox model, both sexes showed a similar all-cause mortality risk [crude hazard ratio (HR): 0.90; 95% confidence interval (CI): 0.72 to 1.12]. However, with respect to specific causes of death, women showed a borderline lower risk of both CVD (crude HR: 0.71; 95% CI: 0.50 to 0.99) and non-CVD mortality from other than infection (crude HR: 0.81; 95% CI: 0.57 to 1.15). In contrast, the risk of death from infection was almost doubled in women compared with men (crude HR: 1.92; 95% CI: 1.15 to 3.20), a finding that held true after multivariate adjustment for age, primary renal disease, period of inclusion, and initial PD modality (adjusted HR: 1.76; 95% CI: 1.03 to 3.01). This result was confirmed even taking into consideration the competing events of kidney transplantation and transfer to hemodialysis. CONCLUSIONS: Compared with men starting PD, women starting PD are at higher risk of mortality from infection. More stringent screening measures and corrective efforts in women might be indicated.

Endocrine alterations and cardiovascular risk in CKD: Is there a link?

The kidney plays an important role in synthesis, metabolism and elimination of a plethora of hormones. Thus, chronic kidney disease (CKD) naturally progresses with hormonal disorders. This review will focus in emerging evidence regarding the association between CKD-associated disturbances in the hypothalamic-pituitary-gonadal axis and cardiovascular risk factors. Hormonal derangements discussed are prolactin retention, testosterone deficiency and the low trioodothyronine syndrome, all of which have traditionally been interpreted as innocent bystanders of uremia and received relatively scarce attention by the Nephrology community. We here show that these disorders share intriguing links with inflammation, endothelial dysfunction, arterial stiffness, protein-energy wasting and other cardiometabolic alterations inherent to CKD-related excess mortality. We argue that these disorders may be novel uremic risk factors with possibility to serve as therapeutic targets (AU)

El riñón tiene un papel importante en la síntesis, metabolismo y eliminación de gran cantidad de hormonas. Así, la enfermedad renal crónica (ERC) cursa de forma natural con diversas alteraciones hormonales. Esta revisión aborda la posible conexión entrealteraciones en el eje hipotalámico-pituitario-gonadal y factores de riesgo cardiovascular en el paciente con ERC. Las anomalías hormonales analizadas son la retención de prolactina, deficiencia de testosterona y síndrome de T3 baja, todas ellas entendidas tradicionalmente como testigos inocentes de uremia y que han recibido una atención relativamente escasa por la comunidad nefróloga. En este revisamos interesantes vinculos entre estas alteraciones hormonales y complicaciones como la inflamación sistemica, la disfunción endotelial, la rigidez arterial, el desgaste proteico-energético y otras alteraciones cardiometabólicas inherentes a la excesiva mortalidad observada en la ERC. Proponemos que estas disfunciones hormonales pueden ser nuevos o previamene no apreciados factores de riesgo en el paciente urémico, existiendo la posibilidad de que puedan servir como objetivos terapéuticos (AU)

Endocrine alterations and cardiovascular risk in CKD: is there a link?

The kidney plays an important role in synthesis, metabolism and elimination of a plethora of hormones. Thus, chronic kidney disease (CKD) naturally progresses with hormonal disorders. This review will focus in emerging evidence regarding the association between CKD-associated disturbances in the hypothalamic-pituitary-gonadal axis and cardiovascular risk factors. Hormonal derangements discussed are prolactin retention, testosterone deficiency and the low trioodothyronine syndrome, all of which have traditionally been interpreted as innocent bystanders of uremia and received relatively scarce attention by the Nephrology community. We here show that these disorders share intriguing links with inflammation, endothelial dysfunction, arterial stiffness, protein-energy wasting and other cardiometabolic alterations inherent to CKD-related excess mortality. We argue that these disorders may be novel uremic risk factors with possibility to serve as therapeutic targets.

Atrial fibrillation and right bundle branch block complicating coil embolization of a huge pulmonary arterio-venous malformation.

Coil embolization is a safe therapy for pulmonary arterio-venous malformations (PAVMs). We report the case of a 72-year-old woman affected by hereditary hemorrhagic teleangectasia who experienced right bundle branch block and atrial fibrillation 36 hours after embolization of an extended PAVM. To our knowledge, this is the first case of such a complication of embolization of a pulmonary fistula, presumably due to an acute pressure overload on both the right atrium and ventricle. This case report suggests that, after embolization of extended pulmonary fistulas, patients should be carefully monitored for rhythm disturbance and new onset of intraventricular conduction defects.