Longitudinal change in proteinuria and kidney outcomes in C3 glomerulopathy

11 p.-4 fig.-4 tab.Introduction: The association between a change in proteinuria over time and its impact in kidney prognosis has not been analyzed in C3 glomerulopathy. This study aims to investigate the association between the longitudinal change in proteinuria and the risk of kidney failure.Methods: Retrospective, multicenter observational cohort study in 35 nephrology departments belonging to the Spanish Group for the Study of Glomerular Diseases (GLOSEN). Patients diagnosed with C3 glomerulopathy between 1995 and 2020 were enrolled. A joint modeling of linear mixed-effects models was applied to assess the underlying trajectory of a repeatedly measured proteinuria, and a Cox model to evaluate the association of this trajectory with the risk of kidney failure.Results: The study group consisted of 85 patients, 70 C3 glomerulonephritis and 15 dense deposit disease, with a median age of 26 years (range 13-41). During a median follow-up of 42 months, 25 patients reached kidney failure. The longitudinal change in proteinuria showed a strong association with the risk of this outcome, with a doubling of proteinuria levels resulting in a 2.5-fold increase of the risk. A second model showed that a ≥ 50% proteinuria reduction over time was significantly associated with a lower risk of kidney failure (HR: 0.79; 95% CI : 0.56-0.97; p < 0.001). This association was also found when the ≥50% proteinuria reduction was observed within the first 6 and 12 months of follow-up.Conclusion: The longitudinal change in proteinuria is strongly associated with the risk of kidney failure. The change in proteinuria over time can provide clinicians a dynamic prediction of kidney outcomes.This study was supported by the Instituto de Salud Carlos III/Fondo Europeo de Desarrollo Regional (ISCIII/FEDER) grant PI16/01685 and PI19/1624, and Red de Investigación Renal (RedInRen) (RD12/0021/0029) (to M.P.), the Autonomous Region of Madrid (S2017/BMD-3673) (to M.P.); E.G.d.J. was supported by the Spanish ‘Ministerio de Ciencia, Innovación y Universidades’ (RYC-2013-13395 and RTI2018-095955-B-100); S.R.d.C. was supported by Ministerio de Economía y Competitividad/FEDER grant SAF2015-66287R and Autonomous Region of Madrid grant S2017/BMD3673.Peer reviewe

Gasdermin-B promotes invasion and metastasis in breast cancer cells

This is an open-access article distributed under the terms of the Creative Commons Attribution License.-- et al.Gasdermin B (GSDMB) belongs to the Gasdermin protein family that comprises four members (GSDMA-D). Gasdermin B expression has been detected in some tumor types such as hepatocarcinomas, gastric and cervix cancers; and its overexpression has been related to tumor progression. At least four splicing isoforms of GSDMB have been identified, which may play differential roles in cancer. However, the implication of GSDMB in carcinogenesis and tumor progression is not well understood. Here, we uncover for the first time the functional implication of GSDMB in breast cancer. Our data shows that high levels of GSDMB expression is correlated with reduced survival and increased metastasis in breast cancer patients included in an expression dataset (>1,000 cases). We demonstrate that GSDMB is upregulated in breast carcinomas compared to normal breast tissue, being the isoform 2 (GSDMB-2) the most differentially expressed. In order to evaluate the functional role of GSDMB in breast cancer two GSDMB isoforms were studied (GSDMB-1 and GSDMB-2). The overexpression of both isoforms in the MCF7 breast carcinoma cell line promotes cell motility and invasion, while its silencing in HCC1954 breast carcinoma cells decreases the migratory and invasive phenotype. Importantly, we demonstrate that both isoforms have a differential role on the activation of Rac-1 and Cdc-42 Rho-GTPases. Moreover, our data support that GSMDB-2 induces a pro-tumorigenic and pro-metastatic behavior in mouse xenograft models as compared to GSDMB-1. Finally, we observed that although both GSDMB isoforms interact in vitro with the chaperone Hsp90, only the GSDMB-2 isoform relies on this chaperone for its stability. Taken together, our results provide for the first time evidences that GSDMB-2 induces invasion, tumor progression and metastasis in MCF7 cells and that GSDMB can be considered as a new potential prognostic marker in breast cancer.This work was supported by grants from the Spanish Ministry of Science and Innovation, MICINN (SAF2007-63075 and SAF2010-20175), AVON Foundation 2012, Comunidad de Madrid (S2010/BMD-2302), AECC network 2011, Instituto de Salud Carlos III (ISCIII) (PI13_00132) to GMB and Breast Network from ISCIII RD12036/0007 to AC. MHR has been funded by a predoctoral contract associated to SAF2007-63075 and now has a postdoc contract from S2010/BMD-23. DS and PGS are funded by postdoc contracts from the AECC Scientific Foundation, AM is funded by a predoctoral fellowship from MECD; ACM is funded by ISCIII RD12036/0007. Dr HP’s work is supported by the Melanoma Research Alliance, Pediatric Oncology Experimental Therapeutics Investigators Consortium, The Nancy C. and Daniel P. Paduano Foundation, The Manning Foundation, NCI (U01 CA169538, RO1 CA169416-01) and the DoD (BC123187, BC121988).Peer Reviewe

Pheochromocytoma-paraganglioma: Biochemical and genetic diagnosis

Pheochromocytomas and paragangliomas are tumours derived from neural crest cells, which can be diagnosed by biochemical measurement of metanephrine and methoxytyramine. Advances in genetic research have identified many genes involved in the pathogenesis of these tumours, suggesting that up to 35–45% may have an underlying germline mutation. These genes have a singular transcriptional signature and can be grouped into 2 clusters (or groups): cluster 1 (VHL and SHDx), involved in angiogenesis and hypoxia pathways; and cluster 2 (MEN2 and NF1), linked to the kinase signalling pathway. In turn, these genes are associated with a characteristic biochemical phenotype (noradrenergic and adrenergic), and clinical features (location, biological behaviour, age of presentation, etc.) in a large number of cases. Early diagnosis of these tumours, accompanied by a correct genetic diagnosis, should eventually become a priority to enable better treatment, early detection of complications, proper screening of family members and related tumours, as well as an improvement in the overall prognosis of these patients

Epicardial fat tissue, coronary arterial calcification and mortality in patients with advanced chronic kidney disease and hemodialysis

Introducción y objetivos El tejido graso epicardico (EAT) y mediastínico (MAT) se relaciona con el síndrome metabólico y la enfermedad arterial coronaria. Los pacientes con enfermedad renal crónica (ERC) tienen mayor volumen de EAT. El objetivo de nuestro estudio fue determinar si estos depósitos adiposos podrían estar relacionados con un aumento de mortalidad y eventos cardiovasculares en pacientes con ERC avanzada y en hemodiálisis. Métodos Se realizó un análisis post hoc de una serie prospectiva, de 104 casos, con una tomografía computarizada sincronizada multicorte (MSCT) que permitiera cuantificar el grosor EAT. Resultados El periodo de seguimiento fue de 112,68 (109,94-115,42) meses. El punto de corte de EAT con mayor sensibilidad y especificidad para predecir mortalidad total fue 11,45mm (el 92,86 y el 43,75%, respectivamente). Las variables que se correlacionaron con el EAT fueron la albúmina, el nivel sérico de triglicéridos, de fósforo y el producto fosfo-cálcico. El EAT fue mayor en pacientes en hemodiálisis respecto aquellos con ERC avanzada (p 11,45mm (p=0,007). Conclusiones Un mayor grosor de EAT y MAT se relacionó con un incremento de mortalidad total. Además, el EAT se asoció con una menor supervivencia libre de eventos cardiovasculares fatales y no fatales. La cuantificación de EAT y MAT mediante MSCT podría tener valor pronóstico para pacientes con ERC avanzada y hemodiálisis.Introduction and objectives Epicardial and mediastinal adipose tissue (EAT, MAT) are linked to metabolic syndrome and coronary artery disease. Patients with chronic kidney disease (CKD) have thicker EAT. We assessed if EAT and MAT could be associated with increased mortality and cardiovascular events in patients with advanced CKD and haemodialysis therapy. Methods A post-hoc study was performed. We analyzed a prospective series of 104 cases. EAT thickness was quantified by a multislice synchronized computed tomography (MSCT). Results The follow-up period was 112.68 (109.94–115.42) months. The optimal cut-off point of EAT for prediction of total mortality was 11.45 mm (92.86% and 43.75%). EAT thickness was associated with serum albumin levels, serum triglyceride levels, phosphorus and calcium phosphate product. The EAT was greater in haemodialysis patients compared to those with advanced CKD (P 11.45 mm (P = .007). Conclusions A higher EAT and MAT thickness was associated with increased mortality. Furthermore, EAT was associated with lower free survival time to fatal and non-fatal cardiovascular events. The measurement of EAT and MAT by MSCT could be a prognostic tool to predict cardiovascular events and mortality risk in advanced CKD patients.Sin financiación2.033 JCR (2019) Q4, 67/89 Urology & Nephrology0.252 SJR (2021) Q3, 49/72 NephrologyNo data IDR 2020UE

Epicardial fat tissue, coronary arterial calcification and mortality in patients with advanced chronic kidney disease and hemodialysis

Introduction and objectives: Epicardial and mediastinal adipose tissue (EAT, MAT) are linked to metabolic syndrome and coronary artery disease. Patients with chronic kidney disease (CKD) have thicker EAT. We assessed if EAT and MAT could be associated with increased mortality and cardiovascular events in patients with advanced CKD and haemodialysis therapy. Methods: A post-hoc study was performed. We analyzed a prospective series of 104 cases. EAT thickness was quantified by a multislice synchronized computed tomography (MSCT). Results: The follow-up period was 112.68 (109.94–115.42) months. The optimal cut-off point of EAT for prediction of total mortality was 11.45 mm (92.86% and 43.75%). EAT thickness was associated with serum albumin levels, serum triglyceride levels, phosphorus and calcium phosphate product. The EAT was greater in haemodialysis patients compared to those with advanced CKD (P  11.45 mm (P = .007). Conclusions: A higher EAT and MAT thickness was associated with increased mortality. Furthermore, EAT was associated with lower free survival time to fatal and non-fatal cardiovascular events. The measurement of EAT and MAT by MSCT could be a prognostic tool to predict cardiovascular events and mortality risk in advanced CKD patients. Resumen: Introducción y objetivos: El tejido graso epicardico (EAT) y mediastínico (MAT) se relaciona con el síndrome metabólico y la enfermedad arterial coronaria. Los pacientes con enfermedad renal crónica (ERC) tienen mayor volumen de EAT. El objetivo de nuestro estudio fue determinar si estos depósitos adiposos podrían estar relacionados con un aumento de mortalidad y eventos cardiovasculares en pacientes con ERC avanzada y en hemodiálisis. Métodos: Se realizó un análisis post hoc de una serie prospectiva, de 104 casos, con una tomografía computarizada sincronizada multicorte (MSCT) que permitiera cuantificar el grosor EAT. Resultados: El periodo de seguimiento fue de 112,68 (109,94-115,42) meses. El punto de corte de EAT con mayor sensibilidad y especificidad para predecir mortalidad total fue 11,45 mm (el 92,86 y el 43,75%, respectivamente). Las variables que se correlacionaron con el EAT fueron la albúmina, el nivel sérico de triglicéridos, de fósforo y el producto fosfo-cálcico. El EAT fue mayor en pacientes en hemodiálisis respecto aquellos con ERC avanzada (p  11,45 mm (p = 0,007). Conclusiones: Un mayor grosor de EAT y MAT se relacionó con un incremento de mortalidad total. Además, el EAT se asoció con una menor supervivencia libre de eventos cardiovasculares fatales y no fatales. La cuantificación de EAT y MAT mediante MSCT podría tener valor pronóstico para pacientes con ERC avanzada y hemodiálisis

Coronary artery calcification in patients with diabetes mellitus and advanced chronic kidney disease

Introducción: Los pacientes con enfermedad renal crónica (ERC) y diabetes mellitus (DM) tienen un elevado riesgo cardiovascular. Ambas enfermedades se relacionan con el desarrollo de ateroesclerosis sistémica y calcificación vascular. La prevalencia y la severidad de la calcificación arterial coronaria (CaC) es mayor en personas con DM, independientemente de su función renal. Los datos acerca del papel pronóstico a largo plazo de la CaC en pacientes con DM y ERC son escasos. Material y métodos: Se diseñó un estudio prospectivo que incluía a 137 pacientes (85 en hemodiálisis y 52 con ERC avanzada). Se realizó una tomografía computerizada (TC) helicoidal multicorte coronario basal. La CaC se cuantificó mediante el método de Agatston y los pacientes fueron clasificados en CaC leve-moderada (CaC < 400 UH) y severa (CaC ≥ 400 UH). Resultados: El tiempo medio de seguimiento fue de 87,5 meses. El 28% eran pacientes con DM; tenían una CaC más severa, menor nivel de albúmina y una proteína C reactiva más elevada. La albúmina se correlacionó con la CaC severa (r = –0,45; p = 0,009). La mortalidad fue del 58%. Los casos con DM mostraban una tendencia lineal de mayor mortalidad en comparación con los sujetos sin DM (Chi cuadrado 3,51, p = 0,061). Los pacientes con DM y CaC severa tuvieron, además, una mayor mortalidad en comparación con aquellos con CaC severa sin DM (93% vs.73%; p = 0,04). Conclusiones: Los pacientes con ERC avanzada y DM presentan una CaC más severa, datos bioquímicos compatibles con una mayor inflamación-malnutrición y una mayor mortalidad en comparación con aquellos sin DM.Introduction: Patients with chronic kidney disease (CKD) and diabetes mellitus (DM) have high cardiovascular risk. Both conditions are related to systemic atherosclerosis and vascular calcification. The prevalence and severity of coronary artery calcification (CaC) is higher in patients with DM, regardless of their renal function. Data about the long-term prognostic role of CaC in diabetic patients with CKD are scarce. Material and methods: We carried out a prospective longitudinal study enrolling 137 patients with advanced CKD. A non-enhanced multislice coronary computed tomography (CT) was performed at baseline. CaC was assessed using Agatston method. Patients were stratified according to their CaC score: severe calcification group (CaCs≥400HU) and mild-moderate calcification group (CaCs<400HU). Results: The median follow-up time was 87.5 months. DM was found in 28% of subjects. The patients with DM showed more severe CaC, lower albumin and higher C-reactive protein serum levels. Serum albumin was correlated with severe CaC (r=-0.45, P=.009). Overall mortality rate reached 58%. Patients with DM also tended to have higher mortality compared to non-diabetic subjects (X2 3.51, P=.061) especially those with severe CaC showed higher mortality than those with severe CaC without DM (93% vs.73%, P=.04). Conclusions: Patients with advanced CKD and DM have more severe CaC, increased inflammation-malnutrition data and higher mortality compared to those without DM. Keywords: Advanced chronic kidney disease; Calcificación arterial coronaria; Coronary arterial calcification; Diabetes mellitus; Enfermedad renal crónica; Hemodialysis; Hemodiálisis; Mortalidad; Mortality.Sin financiación1.180 JCR (2019) Q4, 133/143 Endocrinology & Metabolism0.312 SJR (2019) Q3, 178/245 Endocrinology, Diabetes and MetabolismUE

Coronary calcification as a predictor of cardiovascular mortality in advanced chronic kidney disease: a prospective long-term follow-up study

Background: Patients with advanced chronic kidney disease (CKD) exhibit higher prevalence of coronary artery calcification (CaC) than general population. CaC has been proposed as a risk factor for mortality in end-stage CKD, but most studies in the field are based on short-term follow-up. Methods: We conducted a cohort, 10-year prospective longitudinal study of consecutive cases referred to the renal unit. A non-enhanced multislice coronary computed tomography was performed at baseline. CaC was assessed by Agatston method. Patients were stratified according to their CaC score: severe calcification group (CaCs< 400 HU) and mild-moderate calcification group (CaCs≥400 HU). The overall and cardiovascular (CV) mortality, CV events, and factors potentially associated with CaC development were recorded. Results: 137 patients with advanced CKD were enrolled and provided consent. Overall mortality rate was 58%; 40% due to CV events. The rate of overall mortality in the severe calcification group was 75%, and 30% in the low calcification group, whereas the rate of CV mortality was 35% vs. 6%, respectively (p < 0.001). The severe calcification group was older, had higher prevalence of type 2 diabetes mellitus, former cardiologic events, and lower albumin serum levels than the mild-moderate calcification group. In a multivariate Cox model, severe CaC was a significant predictor of CV mortality (HR 5.01; 95%CI 1.28 to 19.6, p = 0.02). Conclusions: Among advanced CKD, there was a significantly increase of CV mortality in patients with severe CaCs during a 10-year follow-up period. CaCs could be a useful prognostic tool to predict CV mortality risk in CKD patients.Sin financiación1.913 JCR (2019) Q3, 51/85 Urology & Nephrology0.794 SJR (2019) Q2, 22/70 NephrologyNo data IDR 2019UE

Longitudinal change in proteinuria and kidney outcomes in C3 glomerulopathy

11 p.-4 fig.-4 tab.Introduction: The association between a change in proteinuria over time and its impact in kidney prognosis has not been analyzed in C3 glomerulopathy. This study aims to investigate the association between the longitudinal change in proteinuria and the risk of kidney failure.Methods: Retrospective, multicenter observational cohort study in 35 nephrology departments belonging to the Spanish Group for the Study of Glomerular Diseases (GLOSEN). Patients diagnosed with C3 glomerulopathy between 1995 and 2020 were enrolled. A joint modeling of linear mixed-effects models was applied to assess the underlying trajectory of a repeatedly measured proteinuria, and a Cox model to evaluate the association of this trajectory with the risk of kidney failure.Results: The study group consisted of 85 patients, 70 C3 glomerulonephritis and 15 dense deposit disease, with a median age of 26 years (range 13-41). During a median follow-up of 42 months, 25 patients reached kidney failure. The longitudinal change in proteinuria showed a strong association with the risk of this outcome, with a doubling of proteinuria levels resulting in a 2.5-fold increase of the risk. A second model showed that a ≥ 50% proteinuria reduction over time was significantly associated with a lower risk of kidney failure (HR: 0.79; 95% CI : 0.56-0.97; p < 0.001). This association was also found when the ≥50% proteinuria reduction was observed within the first 6 and 12 months of follow-up.Conclusion: The longitudinal change in proteinuria is strongly associated with the risk of kidney failure. The change in proteinuria over time can provide clinicians a dynamic prediction of kidney outcomes.This study was supported by the Instituto de Salud Carlos III/Fondo Europeo de Desarrollo Regional (ISCIII/FEDER) grant PI16/01685 and PI19/1624, and Red de Investigación Renal (RedInRen) (RD12/0021/0029) (to M.P.), the Autonomous Region of Madrid (S2017/BMD-3673) (to M.P.); E.G.d.J. was supported by the Spanish ‘Ministerio de Ciencia, Innovación y Universidades’ (RYC-2013-13395 and RTI2018-095955-B-100); S.R.d.C. was supported by Ministerio de Economía y Competitividad/FEDER grant SAF2015-66287R and Autonomous Region of Madrid grant S2017/BMD3673.Peer reviewe