Enfermedad coronaria en el trasplante renal:incidencia, tipología, factores de riesgo y pronóstico

Programa Oficial de Doutoramento en Ciencias da Saúde. 5007V01[Resumen] INTRODUCCION: La causa más importante de muerte en pacientes trasplantados renales es la mortalidad cardiovascular. La enfermedad coronaria constituye la mayor causa de patología cardiaca en el post‐trasplante, siendo la responsable de angina, infarto, insuficiencia cardiaca o arritmias. OBJETIVO:EL objetivo de esta Tésis es conocer la incidencia de enfermedad coronaria en trasplante renal, los factores de riesgo, la tipología de la afectación y su relación con parámetros clínicos, el tratamiento administrado y el pronóstico, tanto para la supervivencia del paciente como para la supervivencia renal. MATERIAL Y METODOS: Se estudian los pacientes trasplantados en el Hospital Universitario A Coruña desde 1981 hasta 2016. Se define evento coronario como aquel episodio de angina o infarto según características clínicas y datos complementarios. Variables analizadas: incidencia de eventos coronarios y su relación con el período de tiempo de observación, edad del donante y receptor, género, enfermedad de base, tipo de trasplante, trasplante combinado, antecedentes de enfermedad cardiovascular previo, HTA, hábito tabáquico, diabetes pre y post‐trasplante, hipertrofia ventricular izquierda, colesterol, triglicéridos, glucemia, hemoglobina, función retrasada del injerto y duración, creatinina, proteinuria, nº coronarias afectadas, enfermeenfermedad multivaso, tipo de coronaria afectada, porcentaje de estenosis coronaria, fracción de eyección según coronarias afectadas, calcificación valvular, tratamiento realizado: médico, IPC, cirugía by‐pass. Pronóstico según evento coronario y tratamiento efectuado. RESULTADOS: Se estudiaron 2889 pacientes trasplantados renales en el Hospital Universitario de A Coruña desde 1981 hasta 2016.Se registraron 245 eventos coronarios en 35 años, 1,23/100 pacientes año. La incidencia acumulada fue 3,4% a los 3 meses del trasplante, 4,1% al año, 5,3% al tercer año, 6,6% al 5º año, 10,5% al 10º año y 14,5% al 15ª año, según Kaplan‐Meier y Metodología Riesgos Competitivos. Cuando comparamos dos períodos de tiempo (1981‐2001 y 2002‐2016), la incidencia acumulada es menor en el segundo período, 6,8 vs 12,1% al 10 año; p=0,002.La incidencia de eventos es mayor en el primer trimestre 37,9% y esta frecuencia ha aumentado respecto al número total de eventos durante el segundo período un 21,8%. Los factores de riesgo en el análisis de Cox fueron edad, tiempo en lista de trasplante, ECV previa, diabetes post‐trasplante, fumar, colesterol, creatinina y tensión arterial sistólica. Los factores de riesgo para el primer trimestre son la edad, la ECV previa y la presencia de FRI. El cambio evolutivo de los factores de riesgo a lo largo de la evolución hace que cambien los modelos de regresión en el período de tiempo estudiado. La coronaria más afectada es la arteria descendente anterior. No encontramos enfermedad oclusiva en 24,2% y existe enfermedad coronaria de 3 vasos en 27,5%.La fracción de eyección se relaciona negativamente con el nº de vasos afectados y la severidad de la estenosis. En curvas ROC una fracción de eyección inferior al 57% se relaciona con enfermedad de 3 vasos con una sensibilidad de 81% y especificidad del 53,2%. El tratamiento de la enfermedad coronaria fue en el 56,5% sólo tratamiento médico, en el 19,5% cirugía y en el 31% Intervención Percutánea. El tratamiento mediante cirugía fue indicado en pacientes más jóvenes y con enfermedad de tres vasos. La supervivencia del paciente tras presentar un evento coronario es 67,2% al 5º año. La supervivencia del injerto tras presentar un evento coronario es 78,1% al 5º año. En el modelo de regresión de Cox, el uso de cirugía se asoció a menor mortalidad, aunque esta diferencia no fue significativa empleando el modelo de riesgos competitivos. La incidencia acumulada de mortalidad coronaria empleando MRC en el primer período es 2,25 al 6º año. En el segundo período es de 0,84% al 6º año. La causa de muerte de los pacientes tras un evento coronaria es cardíaca en 47,3%. CONCLUSIONES: La incidencia de eventos coronarios ha disminuido en los últimos 15 años así como la mortalidad cardíaca en relación con el control de los factores de riesgo.La frecuencia de eventos coronarios en el primer trimestre ha aumentado porcentualmente en estos últimos años. La enfermedad coronaria de 3 vasos ocurre en el 27.5%. La fracción de eyección se correlaciona con la severidad de la enfermedad coronaria, siendo mayor ésta en los pacientes con infarto. La cirugía es el tratamiento más indicado en pacientes jóvenes y enfermedad coronaria de tres vasos y se se ha asociado a menor mortalidad.La supervivencia del paciente después de presentar un evento coronario es 85,2% al 1 año y 67,2% al 5º año.[Resumo] INTRODUCCION: A causa maiís importante de morte en doentes trasplantados de ril é a mortalidade cardiovascular. A enfermidade coronaria constitúe a maior causa de patoloxía cardíaca no post‐trasplante, sendo a responsable de anxina, infarto, insuficiencia cardíaca ou arritmias. OBXETIVO: O obxetivo desta Tese e coñecer a incidencia da enfermidade coronaria, os factores de risco, a tipoloxía da afectación coronaria, a súa relación con parámetros clínicos, o tratamento administrado e o pronóstico tanto da supervevencia do doente como a do inxerto. MATERIAL E METODOS: Estúdanse os doentes trasplantados de ril no Hospital Universitario A Coruña dende 1981 ata 2016. Defínese evento coronario como aquel episodio de anxina ou infarto segundo as características clínicas e datos complementarios. Variables analizadas: incidencia de eventos coronarios e a súa relación co período de tempo da observación, idade do donante e receptor, xénero, enfermidade de base, tipo de trasplante, trasplante combinado, antecedentes de enfermidade cardiovascular previa, HTA, xeito de fumar, diabetes pre e posttrasplante, hipertrofia ventricular esquerda, colesterol, triglicéridos, glucemia, hemoglobina, función retrasada do inxerto e duración, creatinina, proteinuria, nº coronarias afectadas, enfermidade multivaso, tipo de coronaria afectada, porcentaxe de estenosis coronaria, fracción de eyección segundo coronarias afectadas, calcificación valvular, tratamento realizado: Médico, IPC, cirurxía by‐pass. Pronóstico segundo evento coronario e tratamento efectuado RESULTADOS: Estudáronse 2889 doentes trasplantados de ril no Hospital Universitario de A Coruña dende 1981 ata 2016.Rexistráronse 245 eventos coronarios en 35 anos, 1,23/100 doentes ano. A incidencia acumulada foi 3,4% aos 3 meses do trasplante, 4,1% ao ano, 5,3% ao tercer ano, 6,6% ao 5º ano, 10,5% ao 10º año e 14,5% ao 15ª ano, segundo KM y RC. Cando comparamos os dous períodos de tempo (1981‐2001 e 2002‐2016), a incidencia acumulada é menor no segundo período, 6,8 vs 12,1% no 10 ano; p=0,002.A incidencia de eventos é maior no primeiro trimestre 37,9% e esta frecuencia aumentou respecto ao número total de eventos durante o segundo período un 21,8%. Os factores de risco no análise de Cox foron: idade, tempo en lista de trasplante, ECV previa, diabetes post‐trasplante, o fumar, colesterol, creatinina e tensión arterial sistólica. Os factores de risco para o primeiro trimestre son a idade, a ECV previa e a presencia de FRI.O cambio evolutivo nos factores de risco fai que cambien tamén os modelos de regresión en relación co período de tempo estudado. A coronaria mais afectada é a arteria descendente anterior. Non encontramos enfermidade oclusiva no 24,2% e existe enfermidade coronaria de 3 vasos en 27,5%.A fracción de eyección relaciónase negativamente co nº de vasos afectados e a severidade da estenosis. Nas curvas ROC unha fracción de eyección inferior ao 57% relaciónase coa enfermidade de 3 vasos cunha sensibilidade do 81% e unha especificidade do 53,2%. O tratamento da enfermidade coronaria foi: só tratamento médico en 56,5%, cirurxía en 19,5% e IPC no 31%. O tratamento mediante cirurxía foi indicado en doentes máis xóvenes e con enfermidade de tres vasos. A supervivencia do doente despois de presentar un evento coronario é de 67,2% ao 5º ano. A supervivencia do inxerto tras presentar un evento coronario é 78,1% no 5º ano. No modelo de regresión de Cox, o uso da cirurxía asociouse a menor mortalidade, ainda que esta diferenza non foi significativa cando empregamos o modelo de riscos competitivos. A incidencia acumulada de mortalidade coronaria empregando MRC no primeiro período é de 2,25% ao 6º ano. No segundo período é de 0,84% ao 6º ano. A causa da morte dos doentes despois dun evento coronaro é cardíaca no 47,3%. CONCLUSIONS: A incidencia de eventos coronarios disminuíu nos últimos 15 anos así como a mortalidade cardíaca en relación co control dos factores de risco. A frecuencia de eventos coronarios no primeiro trimestre aumentóu porcentualmente nos últimos anos. A enfermidade enfermidade coronaria de 3 vasos ocorre no 27,5%. Existe unha relación negativa da fracción de eyección coa severidade da enfermidade coronaria, sendo ista maior nos doentes con infarto. A cirurxía é o tratamemnto mais indicado a doentes xóvenes e enfermidade coronaria de tres vasos e asociouse a unha menor mortalidade. A supervivencia do doente despois de presentar un evento coronario é 85,2% no 1º ano e 67,2% no 5º ano.[Abstract] BACKGROUND: The most important cause of dead in renal transplant recipients is the cardiovascular mortality. The coronary disese is the main cause of cardiac pathology after kidney transplantation, being responsible for angor, infarct, heart failure or arrythmias. OBJECTIVE:The aim of this Thesis is to know the coronary disease incidence, the risk factors, the tipology of coronary afecttion and the relationship with clinical parameters, treatment received and outcome so patient survival as allograft survival. MATERIAL AND METHODS: The kidney transplant recipients in Hospital Universitario A Coruña were studied from 1981 to 2016. The coronary event was defined as angor or infarct according to clinic characteristics and complementary data. Parameters analyzed: incidence of coronary events according with the period after kidney transplantation, age (donors and recipients),sex, primary disease, kind of transplant,combined transplant, history of previous cardiovascular disease before transplantation, hypertension, tobacco habit, diabetes, left ventricular hypertrophy, cholesterol, triglycerides, glycemia, hemoglobin, delayed graft function, creatinine, proteinuria, number of affected vessels, multivessel disease, type of coronary artery affected, valvular calcification, ejection fraction, percentage of coronary stenosis, treatment (medical, percutaneous intervention or By‐pass surgery), and the outcome according the coronary event and the treatment administered. RESULTS: 2889 kidney transplant recipients were studied from 1981 to 2016. In this period ( 36 years), 245 coronary events had been registered, 1,23/100 patientsyear. The cumuled incidence was 3,4% at 3rdmonth, 4,1% at 1st year, 5,3% at 3rd year, 6,6% at 5th year, 10,5% at 10th year and 14,5% at 15th year.The cumuled incidence was less in the period 2002‐2016 than the period 1981‐2001: 6,8% vs 12,1% at 10th year (p=0,002).This incidence of coronary events was highest at three months 37,9% and it increased with respect to total events by 21,8% in the second period. (p=0,002). The risk factors found in Cox model were age, time on waiting list, cardiovascular disease before transplantation, cholesterol levels, creatinine, smoking, diabetes after transplantation and Systolic Arterial Tension. The most important risk factors during the first three months after transplantation were age, presence of cardiovascular disease before transplantation and delayed graft function. The change of long‐term risk factors is very important because it makes the regression models change according to the period of study. The most affected coronary artery was the anterior descending artery. Non‐occlusive coronary disease was found in 24, 2 % while there is three vessels coronary disease in 27,5%. The ejection fraction has a negative relationship with the number of affected vessels and with the degree of coronary stenosis.In ROC curves, a ejection fraction less than 57% is associated with three vessels disease with a sensitivity of 81% and specificity of 53,2%. The coronary disease treatment consisted in medical therapy only in 56, 6 %, PCI in 31% and 19, 5% of patients received By‐PASS surgery.This last therapy was indicated more frequently in young people and in patients with three vessels disease.In Cox regression, the use of surgery is associated with less mortality but when we use the competitive risk model it is not significative. The patient survival after presenting a coronary event was 67, 2% at 5th year. The allograft survival was 78, 1% at 5th year. Coronary mortality using a competitive risks model was lower in the period 2002‐2016 vs 1981‐2001: 2, 25% at 6th vs 0, 84% at 6th respectively. CONCLUSIONS: The incidence of coronary disease after kidney transplantation has decreased the last 15 years and mortality too. There is an increment in the percentage of coronary events in the first three months with respect to total events in the second period. The three vessels coronary disease was 27,5%.Threre is a negative relationship between the ejection fraction and severity of coronary disease. Patients with infarct have more severe disease than patients with angor. The treatment with by‐pass is associated to young patients and three vessels disease and it’s a variable associated with lower mortality.The survival patient after coronary event is 85,2% at 1 st year and 67,2% al 5th year

Incidence of cardiovascular events and associated risk factors in kidney transplant patients: a competing risks survival analysis

[Abstract] Background: The high prevalence of cardiovascular risk factors among the renal transplant population accounts for increased mortality. The aim of this study is to determine the incidence of cardiovascular events and factors associated with cardiovascular events in these patients. Methods: An observational ambispective follow-up study of renal transplant recipients (n = 2029) in the health district of A Coruña (Spain) during the period 1981-2011 was completed. Competing risk survival analysis methods were applied to estimate the cumulative incidence of developing cardiovascular events over time and to identify which characteristics were associated with the risk of these events. Post-transplant cardiovascular events are defined as the presence of myocardial infarction, invasive coronary artery therapy, cerebral vascular events, new-onset angina, congestive heart failure, rhythm disturbances, peripheral vascular disease and cardiovascular disease and death. The cause of death was identified through the medical history and death certificate using ICD9 (390-459, except: 427.5, 435, 446, 459.0). Results: The mean age of patients at the time of transplantation was 47.0 ± 14.2 years; 62% were male. 16.5% had suffered some cardiovascular disease prior to transplantation and 9.7% had suffered a cardiovascular event. The mean follow-up period for the patients with cardiovascular event was 3.5 ± 4.3 years. Applying competing risk methodology, it was observed that the accumulated incidence of the event was 5.0% one year after transplantation, 8.1% after five years, and 11.9% after ten years. After applying multivariate models, the variables with an independent effect for predicting cardiovascular events are: male sex, age of recipient, previous cardiovascular disorders, pre-transplant smoking and post-transplant diabetes. Conclusions: This study makes it possible to determine in kidney transplant patients, taking into account competitive events, the incidence of post-transplant cardiovascular events and the risk factors of these events. Modifiable risk factors are identified, owing to which, changes in said factors would have a bearing of the incidence of events

A randomized clinical trial to determine the effectiveness of CO-oximetry and anti-smoking brief advice in a cohort of kidney transplant patients who smoke: study protocol for a randomized controlled trial

Randomized controlled trial[Abstract]Background: The cardiovascular risk in renal transplant patients is increased in patients who continue to smoke after transplantation. The aim of the study is to measure the effectiveness of exhaled carbon monoxide (CO) measurement plus brief advisory sessions, in comparison to brief advice, to reduce smoking exposure and smoking behavior in kidney transplant recipients who smoke. The effectiveness will be measured by: (1) abandonment of smoking, (2) increase in motivation to stop smoking, and (3) reduction in the number of cigarettes smoked per day. Design: a randomized, controlled, open clinical trial with blinded evaluation. Scope: A Coruña Hospital (Spain), reference to renal transplantation in the period 2012-2015. Inclusion criteria: renal transplant patients who smoke in the precontemplation, contemplation or preparation stages according to the Prochaska and DiClemente's Stages of Change model, and who give their consent to participate. Exclusion criteria: smokers attempting to stop smoking, patients with terminal illness or mental disability that prevents them from participating. Randomization: patients will be randomized to the control group (brief advisory session) or the intervention group (brief advisory session plus measuring exhaled CO). The sample target size is n = 112, with 56 patients in each group. Allowing for up to 10 % loss to follow-up, this would provide 80 % power to detect a 13 % difference in attempting to give up smoking outcomes at a two-tailed significance level of 5 %. Measurements: sociodemographic characteristics, cardiovascular risk factors, treatment, rejection episodes, infections, self-reported smoking habit, drug use, level of dependence (the Fagerström test), stage of change (Prochaska and DiClemente's Stages of Change model), and motivation to giving up smoking (the Richmond test). Response: the effectiveness will be evaluated every 3, 6, 9 and 12 months as: pattern of tobacco use (self-reported tobacco use), smoking cessation rates, carbon monoxide (CO) levels in exhaled air measured by CO-oximetry, urinary cotinine tests, nicotine dependence (Fagerström test), motivational stages of change (Prochaska and DiClemente's stages) and motivation to stop smoking (the Richmond test). Analysis: descriptive statistics and linear/logistic multiple regression models will be performed. Clinical relevance will be measured as relative risk reduction, absolute risk reduction and the number needed to treat. Ethics: informed consent of the patients and Ethical Review Board was obtained (code 2011/061). Discussion: Tobacco is a modifiable risk factor that increase the risk of morbidity and mortality in kidney transplant recipients. If effectiveness of CO-oximetry is confirmed to reduce tobacco exposure, we would have an intervention that is easy to use, low cost and with great implications about cardiovascular risk prevention in these patients.Instituto de Salud Carlos III; PI11/0135

Incidence of cardiovascular events after kidney transplantation and cardiovascular risk scores: study protocol

[Abstract] Background: Cardiovascular disease (CVD) is the major cause of death after renal transplantation. Not only conventional CVD risk factors, but also transplant-specific risk factors can influence the development of CVD in kidney transplant recipients. The main objective of this study will be to determine the incidence of post-transplant CVD after renal transplantation and related factors. A secondary objective will be to examine the ability of standard cardiovascular risk scores (Framingham, REGICOR, SCORE, and DORICA) to predict post-transplantation cardiovascular events in renal transplant recipients, and to develop a new score for predicting the risk of CVD after kidney transplantation. Methods/design: Observational prospective cohort study of all kidney transplant recipients in the A Coruna Hospital (Spain) in the period 1981-2008 (2059 transplants corresponding to 1794 patients). The variables included will be: donor and recipient characteristics, chronic kidney disease-related risk factors, pre-transplant and post-transplant cardiovascular risk factors, routine biochemistry, and immunosuppressive, antihypertensive and lipid-lowering treatment. The events studied in the follow-up will be: patient and graft survival, acute rejection episodes and cardiovascular events (myocardial infarction, invasive coronary artery therapy, cerebral vascular events, new-onset angina, congestive heart failure, rhythm disturbances and peripheral vascular disease). Four cardiovascular risk scores were calculated at the time of transplantation: the Framingham score, the European Systematic Coronary Risk Evaluation (SCORE) equation, and the REGICOR (Registre Gironi del COR (Gerona Heart Registry)), and DORICA (Dyslipidemia, Obesity, and Cardiovascular Risk) functions. The cumulative incidence of cardiovascular events will be analyzed by competing risk survival methods. The clinical relevance of different variables will be calculated using the ARR (Absolute Risk Reduction), RRR (Relative Risk Reduction) and NNT (Number Needed to Treat). The ability of different cardiovascular risk scores to predict cardiovascular events will be analyzed by using the c index and the area under ROC curves. Based on the competing risks analysis, a nomogram to predict the probability of cardiovascular events after kidney transplantation will be developed. Discussion: This study will make it possible to determine the post-transplant incidence of cardiovascular events in a large cohort of renal transplant recipients in Spain, to confirm the relationship between traditional and transplant-specific cardiovascular risk factors and CVD, and to develop a score to predict the risk of CVD in these patients.Instituto de Salud Carlos III; PI070986Xunta de Galicia; PS09/26Insituto de Salud Carlos III; G03/170Instituto de Salud Carlos III; RD06/ 001

Randomized Clinical Trial to Determine the Effectiveness of CO-Oximetry and Anti-Smoking Brief Advice in a Cohort of Kidney Transplant Patients who Smoke

[Abstract] Background: measure the efficacy of exhaled carbon monoxide (CO) measurement plus brief advisory sessions to reduce smoking exposure and smoking behaviour in kidney transplant recipients. Methods: Randomized, controlled, open-label clinical trial at a Spanish hospital.Smoking kidney transplant recipients giving their consent to participate were randomized to control (brief advice, n=63) or intervention group (brief advisory session plus measuring exhaled CO, n=59). Measurements: Sociodemographic characteristics, cardiovascular risk factors, treatment, rejection episodes, infections, self-reported smoking, drug use, level of dependence and motivation to stop smoking (Fagerström's and Richmond's test) and stage of change (Prochaska and DiClemente's Stages). Efficacy was assessed at 3, 6, 9 and 12 months as: cotinine test, CO levels in exhaled air, nicotine dependence, motivational stages of change, motivation to stop smoking, pattern of tobacco use and smoking cessation rates. Logistic regression models were computed. Results: At 12 months of follow-up, differences were found in exhaled CO between the intervention and control group(6.1±6.8vs.10.2±9.7ppm;p=0.028). Carboxyhemoglobin levels were lower in the intervention group as well as the positive cotinine test (1.2±1.2%vs.2.0±2.4%;p=0.039),(53.4%vs.74.2%). At 12 months, intervention reduces the probability of a positive urine test by 28%. Conclusions: Co-oximetry is a clinically relevant intervention for reduction of tobacco exposure in kidney transplant recipients.Instituto de Salud Carlos III; PI11 /0135

An expert system for predicting orchard yield and fruit quality and its impact on the Persian lime supply chain

In recent years academics and industrials have shown an interest in agricultural systems and their complex and non-linear nature, aiming to improve production yield in the agricultural field. Innovative strategies and methodological frameworks are thus required to assist farmers in decision making for an efficient and effective resource management. In particular, this research concerns the structural problem of the Persian lime supply chain in Mexico, which still leads to low production yield over short time periods with heterogeneous fruit quality and also to the emergence of excessive middleman businesses arising from a fragmentation between orchard and exporting companies that constitute the first two links in the associated supply chain. Based on the Persian lime production cycle, an Expert System (ES) using Fuzzy Logic involving an inference engine with IF—THEN type rules is presented in this paper. A Mamdani model codifies the decision criteria related to agricultural practices for growing Persian lime in non-irrigated orchards. The ES allows the farmer to boost production in orchards by modeling application scenarios for agricultural practices. A case study based on an exporting company׳s fruit supply is discussed, in which the ES proves to be a useful tool to aid the decision making involved in the application of agricultural practices in the orchard. Results show an increase in production yield and fruit quality in the orchard, as well as a better synchronization between orchard and exporting companies, with a significant impact on inventory levels of fresh fruit in the link Persian lime exporting company

Endoscopic management of bile leaks after liver transplantation: An analysis of two high-volume transplant centers

Bile leak after liver transplantation (LT) is commonly treated with endoscopic retrograde cholangiopancreatography (ERCP); however, there are limited data regarding the optimal treatment strategy

Endoscopic management of bile leaks after liver transplantation: An analysis of two high- volume transplant centers

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/166247/1/ueg2bf00797.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/166247/2/ueg2bf00797-sup-0001.pd

Expanding the genetic spectrum of TUBB1-related thrombocytopenia

β1-Tubulin plays a major role in proplatelet formation and platelet shape maintenance, and pathogenic variants in TUBB1 lead to thrombocytopenia and platelet anisocytosis (TUBB1-RT). To date, the reported number of pedigrees with TUBB1-RT and of rare TUBB1 variants with experimental demonstration of pathogenicity is limited. Here, we report 9 unrelated families presenting with thrombocytopenia carrying 6 β1-tubulin variants, p.Cys12LeufsTer12, p.Thr107Pro, p.Gln423*, p.Arg359Trp, p.Gly109Glu, and p.Gly269Asp, the last of which novel. Segregation studies showed incomplete penetrance of these variants for platelet traits. Indeed, most carriers showed macrothrombocytopenia, some only increased platelet size, and a minority had no abnormalities. Moreover, only homozygous carriers of the p.Gly109Glu variant displayed macrothrombocytopenia, highlighting the importance of allele burden in the phenotypic expression of TUBB1-RT. The p.Arg359Trp, p.Gly269Asp, and p.Gly109Glu variants deranged β1-tubulin incorporation into the microtubular marginal ring in platelets but had a negligible effect on platelet activation, secretion, or spreading, suggesting that β1-tubulin is dispensable for these processes. Transfection of TUBB1 missense variants in CHO cells altered β1-tubulin incorporation into the microtubular network. In addition, TUBB1 variants markedly impaired proplatelet formation from peripheral blood CD34+ cell-derived megakaryocytes. Our study, using in vitro modeling, molecular characterization, and clinical investigations provides a deeper insight into the pathogenicity of rare TUBB1 variants. These novel data expand the genetic spectrum of TUBB1-RT and highlight a remarkable heterogeneity in its clinical presentation, indicating that allelic burden or combination with other genetic or environmental factors modulate the phenotypic impact of rare TUBB1 variants.This work was partially supported by grants from Instituto de Salud Carlos III (ISCIII) and Feder (PI17/01311, PI17/01966, PI20/00926 and CB15/00055), Fundacion Séneca (19873/ GERM/15), Gerencia Regional de Salud (GRS 2061A/19 and 1647/A/17), Fundacion Mutua Madrile´ña (AP172142019), and ~ Sociedad Espanola de Trombosis y Hemostasia (Premio L ~ opez Borrasca 2019 and Ayuda a Grupos de Trabajo en Patologıa Hemorragica). The authors’ research on inherited platelet disorders is conducted in accordance with the aims of the Functional and Molecular Characterization of Patients with Inherited Platelet Disorders Project, from Grupo Espanol de Alteraciones Plaqueta- ~ rias Congenitas, which is supported by the Spanish Society of Thrombosis and Haemostasis. V.P.-B. has a predoctoral contract from CIBERER. L.B. was supported by a fellowship from Fondazione Umberto Veronesi. M.E.d.l.M.-B. holds a postdoctoral fellowship from the University of Murcia. A.M.-Q. holds a predoctoral grant from the Junta de Castilla y Leon

Incidence of cardiovascular events after kidney transplantation and cardiovascular risk scores: study protocol

<p>Abstract</p> <p>Background</p> <p>Cardiovascular disease (CVD) is the major cause of death after renal transplantation. Not only conventional CVD risk factors, but also transplant-specific risk factors can influence the development of CVD in kidney transplant recipients.</p> <p>The main objective of this study will be to determine the incidence of post-transplant CVD after renal transplantation and related factors. A secondary objective will be to examine the ability of standard cardiovascular risk scores (Framingham, Regicor, SCORE, and DORICA) to predict post-transplantation cardiovascular events in renal transplant recipients, and to develop a new score for predicting the risk of CVD after kidney transplantation.</p> <p>Methods/Design</p> <p>Observational prospective cohort study of all kidney transplant recipients in the A Coruña Hospital (Spain) in the period 1981-2008 (2059 transplants corresponding to 1794 patients).</p> <p>The variables included will be: donor and recipient characteristics, chronic kidney disease-related risk factors, pre-transplant and post-transplant cardiovascular risk factors, routine biochemistry, and immunosuppressive, antihypertensive and lipid-lowering treatment. The events studied in the follow-up will be: patient and graft survival, acute rejection episodes and cardiovascular events (myocardial infarction, invasive coronary artery therapy, cerebral vascular events, new-onset angina, congestive heart failure, rhythm disturbances and peripheral vascular disease).</p> <p>Four cardiovascular risk scores were calculated at the time of transplantation: the Framingham score, the European Systematic Coronary Risk Evaluation (SCORE) equation, and the REGICOR (Registre Gironí del COR (Gerona Heart Registry)), and DORICA (Dyslipidemia, Obesity, and Cardiovascular Risk) functions.</p> <p>The cumulative incidence of cardiovascular events will be analyzed by competing risk survival methods. The clinical relevance of different variables will be calculated using the ARR (Absolute Risk Reduction), RRR (Relative Risk Reduction) and NNT (Number Needed to Treat).</p> <p>The ability of different cardiovascular risk scores to predict cardiovascular events will be analyzed by using the c index and the area under ROC curves. Based on the competing risks analysis, a nomogram to predict the probability of cardiovascular events after kidney transplantation will be developed.</p> <p>Discussion</p> <p>This study will make it possible to determine the post-transplant incidence of cardiovascular events in a large cohort of renal transplant recipients in Spain, to confirm the relationship between traditional and transplant-specific cardiovascular risk factors and CVD, and to develop a score to predict the risk of CVD in these patients.</p