Peritoneal protein transport during the baseline peritoneal equilibration test is an accurate predictor of the outcome of peritoneal dialysis patients

[Abstract] Background: Peritoneal protein excretion (PPE) is a potential marker of the outcome in peritoneal dialysis (PD) patients. Method: Observational study of a cohort of 269 patients starting PD in a single unit. Study variables: total PPE during a baseline peritoneal equilibration test (PET; PET-PPE) and 24-hour PPE. Control variables: essential baseline demographic, laboratory and adequacy markers. Main outcomes: mortality, cardiovascular events and risk of peritonitis. We applied univariate and multivariate strategies of survival analysis. Main Results: PET-PPE sustained a significant, yet limited correlation with 24-hour PPE (r = 0.46, p < 0.0005). At baseline, the main study variables showed an independent correlation with peritoneal transport characteristics (D/P240’ creatinine) and cardiovascular comorbidity. PET-PPE (p < 0.0005, model global χ2 59.4) was a more accurate predictor of overall mortality than 24-hour PPE (p = 0.04, χ2 50.5). Moreover, PPE during PET, but not 24-hour PPE, was an independent predictor of the risks of cardiovascular and infectious mortality, and of peritonitis. Conclusions: Baseline PPE represents a strong independent marker of survival of PD patients. Estimation of PPE during PET is more accurate than 24-hour PPE for this purpose, sustains a definite independent association with cardiovascular and infectious mortality, and shows a significant correlation with the risk of peritonitis

La sobrehidratación persistente asocia un riesgo significativo de infección peritoneal por gérmenes entéricos en pacientes tratados con diálisis peritoneal

[Abstract] Background: Overhydration (OH) complicates frequently the clinical course of Peritoneal Dialysis (PD) patients, and keeps a controversial association with the risk of peritoneal infection. The main objective of this study was to disclose an association between persistent OH and the risk of enteric peritonitis in a relatively large sample of patients undergoing PD. Method: Following a prospective design, we monitorized systematically body composition of patients treated with PD in our unit (2011–2016), searching for a correlation with the ensuing risk of peritonitis, with an emphasis on the association between persistent OH (main study variable) and the risk of infection by enteric pathogens (main outcome). Essential demographic, clinical and laboratory variables with a potential influence on the risk of peritonitis were recorded. We used multivariate survival analysis to clarify the specific effect of different body composition parameters on the main outcome. Main results: We included 139 patients for analysis (mean follow-up 24 months). Sixty-three patients suffered at least one peritonitis, and 17 had at least one diagnosis of enteric peritonitis. Univariate analysis disclosed a general trend to an increased risk of enteric peritonitis in overhydrated patients, as evidenced by associations of this outcome with mean extracellular water/intracellular water (ECW/ICW)(p = 0007), OH/ECW (p = 0033) and ECW/total body water (ECW/TBW)(p = 0004) ratios, but not with absolute OH values. Multivariate analysis confirmed similar associations or trends (RR 3,48, 95 % CI 1,03–14,59, p = 0,046, highest versus lowest tertile of ECW/ICW, RR 2,31, 95 % CI 0,98-6,56, p = 0,061, highest versus lowest tertile of OH/ECW, and RR 6,33, 95 % CI 1,37-19,37, p = 0,011, highest versus lowest tertile of ECW/TBW). On the contrary, no apparent association was detected between OH and the overall risk of peritoneal infection.[Resumen] Antecedentes y objetivos. La sobrehidratación (SH) es frecuente, y a menudo persistente, en pacientes tratados con diálisis peritoneal (DP), y mantiene una asociación controvertida con el riesgo de infección peritoneal. El objetivo principal de este estudio fue desvelar una posible asociación entre la presencia de SH y el riesgo subsiguiente de infección peritoneal por gérmenes entéricos, en una población relativamente amplia de pacientes tratados con DP. Método Según diseño prospectivo, monitorizamos de manera sistemática la composición corporal de pacientes tratados con DP en nuestra unidad (2011-2016), buscando una posible correlación con el riesgo de peritonitis durante el seguimiento, con un interés particular en la asociación entre SH persistente (variable de estudio principal) y el riesgo de infección peritoneal por patógenos entéricos (variable resultado principal). Para el análisis tuvimos en cuenta variables demográficas, clínicas y de laboratorio con influencia potencial en el riesgo de infección peritoneal. Utilizamos técnicas de análisis multivariante para clarificar el efecto específico de diferentes parámetros de composición corporal sobre la variable resultado principal. Resultados principales. Incluimos 139 pacientes, con seguimiento medio de 24 meses. Sesenta y tres pacientes sufrieron al menos una peritonitis, y 17 al menos una infección por gérmenes entéricos. El análisis univariante mostró una tendencia general a mayor riesgo de infección peritoneal entérica en pacientes sobrehidratados, que se hacía evidente cuando se usaba el cociente agua extracelular/agua intracelular (AEC/AIC) (p=0,007), el cociente SH/AEC (SH/AEG) (p=0,033), o el cociente AEC/agua corporal total (AEC/ACT) (p=0,004), pero no cuando se usaba la SH absoluta, como variable de estudio. El análisis multivariante confirmó estas asociaciones o tendencias (RR: 3,48; IC 95%: 1,03-14,59; p=0,046, tercil mayor versus menor para AEC/AIC, RR: 2,31; IC 95%: 0,98-6,56; p=0,061, tercil mayor versus menor para SH/AEC, y RR: 6,33; IC 95%: 1,37-19,37; p=0,011, tercil mayor versus menor para AEC/ACT). Por el contrario, no observamos asociación consistente entre SH y riesgo general de infección peritoneal. Conclusión. La SH persistente asocia un riesgo significativo de infección peritoneal por patógenos entéricos, en pacientes tratados con DP

Met signaling in cardiomyocytes is required for normal cardiac function in adult mice.

Hepatocyte growth factor (HGF) and its receptor, Met, are key determinants of distinct developmental processes. Although HGF exerts cardio-protective effects in a number of cardiac pathologies, it remains unknown whether HGF/Met signaling is essential for myocardial development and/or physiological function in adulthood. We therefore investigated the requirement of HGF/Met signaling in cardiomyocyte for embryonic and postnatal heart development and function by conditional inactivation of the Met receptor in cardiomyocytes using the Cre-α-MHC mouse line (referred to as α-MHCMet-KO). Although α-MHCMet-KO mice showed normal heart development and were viable and fertile, by 6 months of age, males developed cardiomyocyte hypertrophy, associated with interstitial fibrosis. A significant upregulation in markers of myocardial damage, such as β-MHC and ANF, was also observed. By the age of 9 months, α-MHCMet-KO males displayed systolic cardiac dysfunction. Mechanistically, we provide evidence of a severe imbalance in the antioxidant defenses in α-MHCMet-KO hearts involving a reduced expression and activity of catalase and superoxide dismutase, with consequent reactive oxygen species accumulation. Similar anomalies were observed in females, although with a slower kinetics. We also found that Met signaling down-regulation leads to an increase in TGF-β production and a decrease in p38MAPK activation, which may contribute to phenotypic alterations displayed in α-MHCMet-KO mice. Consistently, we show that HGF acts through p38α to upregulate antioxidant enzymes in cardiomyocytes. Our results highlight that HGF/Met signaling in cardiomyocytes plays a physiological cardio-protective role in adult mice by acting as an endogenous regulator of heart function through oxidative stress control.Comunidad de Madrid/Universidad Complutense de Madrid; Association Française contre les Myopathies; Seventh Framework Programme; Fondation pour la Recherche Médicale; Instituto de Salud Carlos III; Ministerio de Ciencia e Innovación; Fondation Bettencourt Schueller; European Regional Development Fund; Junta de Andalucía; Junta de Castilla y Leó

De-Intensification of Antidiabetic Treatment Using Canagliflozin in Patients with Heart Failure and Type 2 Diabetes: Cana-Switch-HF Study

Canagliflozin is a sodium-glucose co-transporter 2 inhibitor that reduces glycemia as well as the risk of cardiovascular events. Our main objective was to analyze antidiabetic treatment de-intensification and the glycemic efficacy of replacing antidiabetic agents (excluding metformin) with canagliflozin in patients with heart failure and type 2 diabetes with poor glycemic control. In this observational, retrospective, real-world study, we selected patients treated with metformin in combination with ≥2 non-insulin antidiabetic agents or metformin in combination with basal insulin plus ≥1 non-insulin antidiabetic agent. Non-insulin antidiabetic agents were replaced with canagliflozin. Patients were followed-up on at three, six, and 12 months after the switch and a wide range of clinical variables were recorded. A total of 121 patients were included. From baseline to 12 months, the number of antidiabetic agents (3.1 ± 1.0 vs. 2.1 ± 0.8, p < 0.05), basal insulin dose (20.1 ± 9.8 vs. 10.1 ± 6.5 units, p < 0.01), and percentage of patients who used basal insulin (47.9% vs. 31.3%, p < 0.01) decreased. The proportion of patients who used diuretics also declined significantly. In addition, we observed improvement in glycemic control, with an increase in the proportion of patients with glycated hemoglobin <7% from 16.8% at three months to 63.5% at 12 (p < 0.001). Canagliflozin use was also beneficial in terms of body weight, blood pressure, heart failure status, functional class, and cardiovascular-renal risk. There were also reductions in the number of emergency department visits and hospitalizations for heart failure. Moreover, canagliflozin was well-tolerated, with a low rate of drug-related discontinuation. Mounting evidence from randomized controlled trials and real-world studies point to the beneficial profile of sodium-glucose co-transporter type 2 inhibitors such as canagliflozin in patients with heart failure.This work was supported by PI15/00256 from the Institute of Health “Carlos III” (ISCIII), co-funded by the Fondo Europeo de Desarrollo Regional-FEDER. Maria Isabel Queipo-Ortuño was supported by the “Miguel Servet Type II” program (CPI18/00003, ISCIII, Spain, co-funded by the Fondo Europeo de Desarrollo Regional-FEDER) and by the “Nicolas Monardes” research program of the Consejería de Salud (C-0030-2018, Junta de Andalucía, Spain. Bruno Ramos Molina was supported by the “Miguel Servet Type I” program (CP19/00098, ISCIII, Spain, co-funded by the Fondo Europeo de Desarrollo Regional-FEDER). Lidia Sanchez-Alcoholado was the recipient of a predoctoral grant (PE-0106-2019) from the Consejería de Salud y Familia (co-funded by the Fondo Europeo de Desarrollo Regional-FEDER, Andalucia, Spain). Aurora Laborda-Illanes was the recipient of a predoctoral grant, PFIS-ISCIII (FI19-00112), co-funded by the Fondo Europeo de Desarrollo Regional-FEDER, Madrid, Spain.Ye

Identification of new risk loci shared across systemic vasculitides points towards potential target genes for drug repurposing

Objectives The number of susceptibility loci currently associated with vasculitis is lower than in other immune-mediated diseases due in part to small cohort sizes, a consequence of the low prevalence of vasculitides. This study aimed to identify new genetic risk loci for the main systemic vasculitides through a comprehensive analysis of their genetic overlap. Methods Genome-wide data from 8467 patients with any of the main forms of vasculitis and 29 795 healthy controls were meta-analysed using ASSET. Pleiotropic variants were functionally annotated and linked to their target genes. Prioritised genes were queried in DrugBank to identify potentially repositionable drugs for the treatment of vasculitis. Results Sixteen variants were independently associated with two or more vasculitides, 15 of them representing new shared risk loci. Two of these pleiotropic signals, located close to CTLA4 and CPLX1, emerged as novel genetic risk loci in vasculitis. Most of these polymorphisms appeared to affect vasculitis by regulating gene expression. In this regard, for some of these common signals, potential causal genes were prioritised based on functional annotation, including CTLA4, RNF145, IL12B, IL5, IRF1, IFNGR1, PTK2B, TRIM35, EGR2 and ETS2, each of which has key roles in inflammation. In addition, drug repositioning analysis showed that several drugs, including abatacept and ustekinumab, could be potentially repurposed in the management of the analysed vasculitides. Conclusions We identified new shared risk loci with functional impact in vasculitis and pinpointed potential causal genes, some of which could represent promising targets for the treatment of vasculitis.This work was supported by the HELICAL Innovative Training Network, a European Commission funded project under the Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 813545, the Cooperative Research Thematic Network programme (RD16/0012/0013), Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS) (RD21/0002/0039) and by grant PI18/00040 funded by Instituto de Salud Carlos III. LO-F was supported by Juan de la Cierva Incorporación fellowship (IJC2019-040746-I) funded by MCIN/AEI /10.13039/501100011033.AHS is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health grant number R01 AR070148. DB is supported by a National Health and Medical Research Council (Australia) Investigator Grant (GTN1175744). Research at Murdoch Children’s Research Institute is supported by the Victorian Government’s Operational Infrastructure Support Program. The Vasculitis Clinical Research Consortium (VCRC) received funding as part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), National Center for Advancing Translational Science (NCATS) and received funds from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), U54 AR057319) and the National Center for Research Resources (U54 RR019497)Peer reviewe

Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis

In this study, 1,833 systemic sclerosis (SSc) cases and 3,466 controls were genotyped with the Immunochip array. Classical alleles, amino acid residues, and SNPs across the human leukocyte antigen (HLA) region were imputed and tested. These analyses resulted in a model composed of six polymorphic amino acid positions and seven SNPs that explained the observed significant associations in the region. In addition, a replication step comprising 4,017 SSc cases and 5,935 controls was carried out for several selected non-HLA variants, reaching a total of 5,850 cases and 9,401 controls of European ancestry. Following this strategy, we identified and validated three SSc risk loci, including DNASE1L3 at 3p14, the SCHIP1-IL12A locus at 3q25, and ATG5 at 6q21, as well as a suggested association of the TREH-DDX6 locus at 11q23. The associations of several previously reported SSc risk loci were validated and further refined, and the observed peak of association in PXK was related to DNASE1L3. Our study has increased the number of known genetic associations with SSc, provided further insight into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci

Protective Role of the Interleukin 33 rs3939286 Gene Polymorphism in the Development of Subclinical Atherosclerosis in Rheumatoid Arthritis Patients

OBJECTIVES: To determine whether the interleukin-33 (IL-33)-interleukin-1 receptor like 1 (IL-1RL1) signaling pathway is implicated in the risk of subclinical atherosclerosis in patients with rheumatoid arthritis (RA). METHODS: A total of 576 Spanish RA patients from Northern Spain were genotyped for 6 well-known IL33-IL1RL1 polymorphisms (IL33 rs3939286, IL33 rs7025417, IL33 rs7044343, IL1RL1 rs2058660, IL1RL1 rs2310173 and IL1RL1 rs13015714) by TaqMan genotyping assay. The presence of subclinical atherosclerosis was determined by the assessment of carotid intima-media thickness (cIMT) by carotid ultrasound (US). RESULTS: RA patients carrying the TT genotype of the IL33 rs3939286 polymorphism had lower cIMT values than those homozygous for the CC genotype (mean ± standard deviation (SD): 0.71 ± 0.14 mm versus 0.76 ± 0.16 mm, respectively) while patients carrying the CT genotype had intermediate cIMT values (mean ± SD: 0.73 ± 0.17 mm). Moreover, RA patients carrying the mutant allele T of the IL33 rs3939286 polymorphism exhibited significantly lower cIMT values than those carrying the wild allele C (mean ± SD: 0.72 ± 0.16 mm versus 0.75 ± 0.18 mm respectively; p = 0.04). The association of both genotype and allele frequencies of IL33 rs3939286 and cIMT levels remained statistically significant after adjustment for sex, age at the time of US study, follow-up and center (p = 0.006 and p = 0.0023, respectively), evidencing that the potential effect conferred by IL33 rs3939286 may be independent of confounder factors. No association with other IL33-IL1RL1 genetic variants was observed. CONCLUSIONS: In conclusion, our results may suggest a potential protective effect of the IL33 rs3939286 allele T in the risk of subclinical atherosclerosis in patients with RA

A crowdsourcing database for the copy-number variation of the spanish population

Background: Despite being a very common type of genetic variation, the distribution of copy-number variations (CNVs) in the population is still poorly understood. The knowledge of the genetic variability, especially at the level of the local population, is a critical factor for distinguishing pathogenic from non-pathogenic variation in the discovery of new disease variants. Results: Here, we present the SPAnish Copy Number Alterations Collaborative Server (SPACNACS), which currently contains copy number variation profiles obtained from more than 400 genomes and exomes of unrelated Spanish individuals. By means of a collaborative crowdsourcing effort whole genome and whole exome sequencing data, produced by local genomic projects and for other purposes, is continuously collected. Once checked both, the Spanish ancestry and the lack of kinship with other individuals in the SPACNACS, the CNVs are inferred for these sequences and they are used to populate the database. A web interface allows querying the database with different filters that include ICD10 upper categories. This allows discarding samples from the disease under study and obtaining pseudo-control CNV profiles from the local population. We also show here additional studies on the local impact of CNVs in some phenotypes and on pharmacogenomic variants. SPACNACS can be accessed at: http://csvs.clinbioinfosspa.es/spacnacs/. Conclusion: SPACNACS facilitates disease gene discovery by providing detailed information of the local variability of the population and exemplifies how to reuse genomic data produced for other purposes to build a local reference database.This work is supported by Grants PID2020-117979RB-I00 from the Spanish Ministry of Science and Innovation; by the Institute of Health Carlos III (project IMPaCT-Data, exp. IMP/00019, IMP/00009 and PI20/01305), co-funded by the European Union, European Regional Development Fund (ERDF, “A way to make Europe”)

Mortality and other adverse outcomes in patients with type 2 diabetes mellitus admitted for COVID-19 in association with glucose-lowering drugs: a nationwide cohort study

Background: Limited evidence exists on the role of glucose-lowering drugs in patients with COVID-19. Our main objective was to examine the association between in-hospital death and each routine at-home glucose-lowering drug both individually and in combination with metformin in patients with type 2 diabetes mellitus admitted for COVID-19. We also evaluated their association with the composite outcome of the need for ICU admission, invasive and non-invasive mechanical ventilation, or in-hospital death as well as on the development of in-hospital complications and a long-time hospital stay. Methods: We selected all patients with type 2 diabetes mellitus in the Spanish Society of Internal Medicine's registry of COVID-19 patients (SEMI-COVID-19 Registry). It is an ongoing, observational, multicenter, nationwide cohort of patients admitted for COVID-19 in Spain from March 1, 2020. Each glucose-lowering drug user was matched with a user of other glucose-lowering drugs in a 1:1 manner by propensity scores. In order to assess the adequacy of propensity score matching, we used the standardized mean difference found in patient characteristics after matching. There was considered to be a significant imbalance in the group if a standardized mean difference > 10% was found. To evaluate the association between treatment and study outcomes, both conditional logit and mixed effect logistic regressions were used when the sample size was ≥ 100. Results: A total of 2666 patients were found in the SEMI-COVID-19 Registry, 1297 on glucose-lowering drugs in monotherapy and 465 in combination with metformin. After propensity matching, 249 patients on metformin, 105 on dipeptidyl peptidase-4 inhibitors, 129 on insulin, 127 on metformin/dipeptidyl peptidase-4 inhibitors, 34 on metformin/sodium-glucose cotransporter 2 inhibitor, and 67 on metformin/insulin were selected. No at-home glucose-lowering drugs showed a significant association with in-hospital death; the composite outcome of the need of intensive care unit admission, mechanical ventilation, or in-hospital death; in-hospital complications; or long-time hospital stays. Conclusions: In patients with type 2 diabetes mellitus admitted for COVID-19, at-home glucose-lowering drugs showed no significant association with mortality and adverse outcomes. Given the close relationship between diabetes and COVID-19 and the limited evidence on the role of glucose-lowering drugs, prospective studies are needed