Importância da vitamina D no controlo da asma

Trabalho de revisão do 6º ano médico com vista à atribuição do grau de mestre (área científica de pneumologia) no âmbito do ciclo de estudos de Mestrado Integrado em Medicina.Introdução: A asma é um problema de saúde pública a nível mundial, afetando aproximadamente 300 milhões de pessoas no mundo, cuja prevalência e gravidade têm aumentado desde 1960. Existem inúmeros mecanismos imunopatológicos implicados no seu desenvolvimento, havendo evidência de que a Vitamina D interfere com a função respiratória e a sua deficiência pode contribuir para o maior grau de gravidade da asma. Objetivos: Avaliar o impacto da vitamina D no controlo da asma. Materiais e Métodos: Realizou-se um estudo observacional transversal exploratório de doentes recrutados da Consulta de Pneumologia e de Asma Difícil/Severa do Serviço de Pneumologia do Centro Hospitalar da Universidade de Coimbra, dos Hospitais da Universidade de Coimbra (CHUC-HUC), cujo doseamento sérico da vitamina D constasse no processo clínico. Os dados clínicos de controlo da asma e os parâmetros funcionais respiratórios e laboratoriais correspondentes à data de doseamento foram recolhidos a partir dos processos clínicos, pelo investigador. Os dados foram analisados com base nos métodos estatísticos apropriados, recorrendo ao SPSS ® (Statistical Package for the Social Sciences), software for windows, versão 22.0. Resultados: Incluíram-se 21 doentes asmáticos, classificados como graves, a média de idades foi de 48±14,45 anos, sendo dois terços do sexo feminino. O valor médio de vitamina D foi de 28,2±21,35 U/l, sendo que 78,6% da população apresentava valores compatíveis com deficiência da mesma. Não se verificaram correlações estatisticamente significativas entre o nível de vitamina D e os seguintes parâmetros analisados: FEV1 (Forced Expiratory Volume in the First Second) e VR (Volume Residual), exacerbações da doença, ACT (Asthma Control Test) e CARAT (Control of Allergic Rhinitis and Asthma Test), dose de corticoterapia, IMC (Índice de Massa Corporal - Kg/m2), FeNO (Fração Expiratória de Óxido Nítrico) e eosinófilos no sangue periférico. Registou-se correlação positiva e forte (p=0,022) com o valor de IgE. Discussão e Conclusão: Havendo evidência conflituante sobre a matéria, os resultados obtidos não estão de acordo com a maioria dos artigos publicados, onde se verifica a existência de uma correlação positiva entre níveis deficientes de vitamina D e maior gravidade e pior controlo da asma. Uma possível explicação será o reduzido número da amostra e a grande percentagem de doentes graves, limitando a comparação com asmáticos ligeiros e moderados. Background: Asthma is a public health problem worldwide, affecting approximately 300 million people, and its prevalence and severity have increased since 1960. There are numerous pathogenic mechanisms involved in its development, there is evidence that vitamin D interferes with respiratory function and its deficiency may contribute to the higher degree of severity of asthma. Objectives: Assess the impact of vitamin D in control of asthma disease. Methods: Exploratory cross-sectional observational study enrolled patients of Pulmonology and Severe Asthma consultation from Pulmonology Department of Centro Hospitalar da Universidade de Coimbra, dos Hospitais da Universidade de Coimbra (CHUC-HUC), with serum Vitamin D value present in the clinical process. Clinical data and respiratory and laboratory functional parameters, were collected from medical records, by the investigator. Data were analyzed on the basis of suitable statistical methods, using the SPSS ® (Statistical Package for the Social Sciences), software for windows, version 22.0. Results: The study included a sample of 21 patients, classified as severe, the overall mean age was 48 ± 14.45 years and two-thirds were female. The average value of vitamin D was 28.21 ± 21.35 U / l and 78.6% of the population had values compatible with deficient vitamin D. There were no statistically significant correlations between vitamin D and the following analyzed parameters: FEV1 (Forced Expiratory Volume in the first second) and RV (Residual Volume), disease exacerbations, ACT (Asthma Control Test) and CARAT (Control of Allergic Rhinitis and Asthma Test), corticosteroids, BMI (Body Mass Index - kg/m2), FeNO (Fractional exhaled nitric oxide) and eosinophils in the peripheral blood. There was a positive and strong correlation (p = 0.022) with measured IgE value. Discussion and Conclusion: Despite the conflicting evidence on this matter, the obtained results are not in line with the majority of published articles, where there is the existence of a positive relationship between deficient levels of vitamin D and increased severity and poor asthma control. One possible explanation is the small sample size and the large percentage of severe asthmatics, limiting the comparison with mild to moderate asthma patients

Importância da vitamina D no controlo da asma

Trabalho de revisão do 6º ano médico com vista à atribuição do grau de mestre (área científica de pneumologia) no âmbito do ciclo de estudos de Mestrado Integrado em Medicina.Introdução: A asma é um problema de saúde pública a nível mundial, afetando aproximadamente 300 milhões de pessoas no mundo, cuja prevalência e gravidade têm aumentado desde 1960. Existem inúmeros mecanismos imunopatológicos implicados no seu desenvolvimento, havendo evidência de que a Vitamina D interfere com a função respiratória e a sua deficiência pode contribuir para o maior grau de gravidade da asma. Objetivos: Avaliar o impacto da vitamina D no controlo da asma. Materiais e Métodos: Realizou-se um estudo observacional transversal exploratório de doentes recrutados da Consulta de Pneumologia e de Asma Difícil/Severa do Serviço de Pneumologia do Centro Hospitalar da Universidade de Coimbra, dos Hospitais da Universidade de Coimbra (CHUC-HUC), cujo doseamento sérico da vitamina D constasse no processo clínico. Os dados clínicos de controlo da asma e os parâmetros funcionais respiratórios e laboratoriais correspondentes à data de doseamento foram recolhidos a partir dos processos clínicos, pelo investigador. Os dados foram analisados com base nos métodos estatísticos apropriados, recorrendo ao SPSS ® (Statistical Package for the Social Sciences), software for windows, versão 22.0. Resultados: Incluíram-se 21 doentes asmáticos, classificados como graves, a média de idades foi de 48±14,45 anos, sendo dois terços do sexo feminino. O valor médio de vitamina D foi de 28,2±21,35 U/l, sendo que 78,6% da população apresentava valores compatíveis com deficiência da mesma. Não se verificaram correlações estatisticamente significativas entre o nível de vitamina D e os seguintes parâmetros analisados: FEV1 (Forced Expiratory Volume in the First Second) e VR (Volume Residual), exacerbações da doença, ACT (Asthma Control Test) e CARAT (Control of Allergic Rhinitis and Asthma Test), dose de corticoterapia, IMC (Índice de Massa Corporal - Kg/m2), FeNO (Fração Expiratória de Óxido Nítrico) e eosinófilos no sangue periférico. Registou-se correlação positiva e forte (p=0,022) com o valor de IgE. Discussão e Conclusão: Havendo evidência conflituante sobre a matéria, os resultados obtidos não estão de acordo com a maioria dos artigos publicados, onde se verifica a existência de uma correlação positiva entre níveis deficientes de vitamina D e maior gravidade e pior controlo da asma. Uma possível explicação será o reduzido número da amostra e a grande percentagem de doentes graves, limitando a comparação com asmáticos ligeiros e moderados. Background: Asthma is a public health problem worldwide, affecting approximately 300 million people, and its prevalence and severity have increased since 1960. There are numerous pathogenic mechanisms involved in its development, there is evidence that vitamin D interferes with respiratory function and its deficiency may contribute to the higher degree of severity of asthma. Objectives: Assess the impact of vitamin D in control of asthma disease. Methods: Exploratory cross-sectional observational study enrolled patients of Pulmonology and Severe Asthma consultation from Pulmonology Department of Centro Hospitalar da Universidade de Coimbra, dos Hospitais da Universidade de Coimbra (CHUC-HUC), with serum Vitamin D value present in the clinical process. Clinical data and respiratory and laboratory functional parameters, were collected from medical records, by the investigator. Data were analyzed on the basis of suitable statistical methods, using the SPSS ® (Statistical Package for the Social Sciences), software for windows, version 22.0. Results: The study included a sample of 21 patients, classified as severe, the overall mean age was 48 ± 14.45 years and two-thirds were female. The average value of vitamin D was 28.21 ± 21.35 U / l and 78.6% of the population had values compatible with deficient vitamin D. There were no statistically significant correlations between vitamin D and the following analyzed parameters: FEV1 (Forced Expiratory Volume in the first second) and RV (Residual Volume), disease exacerbations, ACT (Asthma Control Test) and CARAT (Control of Allergic Rhinitis and Asthma Test), corticosteroids, BMI (Body Mass Index - kg/m2), FeNO (Fractional exhaled nitric oxide) and eosinophils in the peripheral blood. There was a positive and strong correlation (p = 0.022) with measured IgE value. Discussion and Conclusion: Despite the conflicting evidence on this matter, the obtained results are not in line with the majority of published articles, where there is the existence of a positive relationship between deficient levels of vitamin D and increased severity and poor asthma control. One possible explanation is the small sample size and the large percentage of severe asthmatics, limiting the comparison with mild to moderate asthma patients

Strategies to Overcome HLA Sensitization and Improve Access to Retransplantation after Kidney Graft Loss

An increasing number of patients waitlisted for kidney transplantation have a previously failed graft. Retransplantation provides a significant improvement in morbidity, mortality, and quality of life when compared to dialysis. However, HLA sensitization is a major barrier to kidney retransplantation and the majority of the highly sensitized patients are waiting for a subsequent kidney transplant. A multidisciplinary team that includes immunogeneticists, transplant nephrologists and surgeons, and adequate allocation policies is fundamental to increase access to a kidney retransplant. A review of Pubmed, ScienceDirect, and the Cochrane Library was performed on the challenges of kidney retransplantation after graft loss, focusing on the HLA barrier and new strategies to overcome sensitization. Conclusion: Technical advances in immunogenetics, new desensitization protocols, and complex allocation programs have emerged in recent years to provide a new hope to kidney recipients with a previously failed graft

Challenges in the Management of the Patient with a Failing Kidney Graft: A Narrative Review

Patients with a failed kidney allograft have steadily increase in recent years and returning to dialysis after graft loss is one of the most difficult transitions for chronic kidney disease patients and their assistant physicians. The management of these patients is complex and encompasses the treatment of chronic kidney disease complications, dialysis restart and access planning, immunosuppression withdrawal, graft nephrectomy, and evaluation for a potential retransplant. In recent years, several groups have focused on the management of the patient with a failing renal graft and expert recommendations are arising. A review of Pubmed, ScienceDirect and the Cochrane Library was performed focusing on the specific care of these patients, from the management of low clearance complications to concerns with a subsequent kidney transplant. Conclusion: There is a growing interest in the failing renal graft and new approaches to improve these patients’ outcomes are being defined including specific multidisciplinary programs, individualized immunosuppression withdrawal schemes, and strategies to prevent HLA sensitization and increase retransplant rates

A Case of Deficiency of Adenosine Deaminase 2: 28 years of Diagnostic Challenges

Deficiency of adenosine deaminase 2 (DADA2) is a unique monogenic autoinflammatory disease caused by autosomal recessive loss-of-function mutations in the CECR1 gene which presents as childhood-onset small- and medium-vessel vasculitis. Previously, many of these patients were misdiagnosed and thought to have clinical features of systemic polyarteritis nodosum, which negatively influenced its outcome, since TNF inhibitors seem to have efficacy on the vasculitic phenotype of DADA2. We present a case of a 28-year-old woman with a lifelong unknown syndrome and unique clinical manifestations recently recognized as DADA2. The first manifestation, at 3 months of age, was an episode of facial paralysis during which renovascular hypertension was diagnosed. Later, she developed episodes of prolonged fever, polyarthritis, Raynaud's phenomenon, gastrointestinal bleeding, and intracerebral hemorrhage. This inflammatory state ultimately led to the development of amyloid A amyloidosis and renal insufficiency

Renal arcuate vein thrombosis–induced acute kidney injury: a rare multiple-Hit–mediated disease

International audienceBackgroundRenal arcuate vein thrombosis (RAVT) is a rare and recently recognized cause of acute kidney injury (AKI) in young adults. However, the precise incidence and underlying pathophysiologic mechanisms leading to AKI in these patients remain elusive.MethodsThis study included all patients who underwent a kidney biopsy over a 40-month period sent to the pathology department of Necker-Enfants Malades Hospital, with evidence of RAVT. We performed coagulation tests, genetic testing for thrombophilia, complete urine toxicologic screening and kidney metagenomic sequencing to identify an underlying cause of thrombosis.ResultsWe report five pediatric cases of RAVT discovered on kidney biopsy performed in the setting of unexplained AKI. Investigations did not reveal an underlying cause of thrombosis but only a significant nonsteroidal anti-inflammatory drugs (NSAIDs) use was reported in 4/5 patients, supporting a potential link between NSAIDs use and RAVT. By performing metagenomic sequencing on kidney biopsy samples, we detected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA in the kidney of one patient. These results suggest that systemic SARS-CoV-2 infection may also be a key contributing factor of renal thrombosis, particularly by inducing potential endothelial disruption.ConclusionsIn conclusion, RAVT-induced AKI appears to be a multiple hit–mediated disease in which NSAIDs consumption and viral infection such as SARS-CoV-2 may be crucial contributing factors. These findings may have significant public health implications given the prevalence of NSAIDs use in the general population. Increased awareness and additional study of future cases may lead to a better understanding of this rare cause of AKI in children and young adults

Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2-year results from a randomised, active-controlled, phase 3 trial

BackgroundSparsentan, a novel, non-immunosuppressive, single-molecule, dual endothelin angiotensin receptor antagonist, significantly reduced proteinuria versus irbesartan, an angiotensin II receptor blocker, at 36 weeks (primary endpoint) in patients with immunoglobulin A nephropathy in the phase 3 PROTECT trial's previously reported interim analysis. Here, we report kidney function and outcomes over 110 weeks from the double-blind final analysis.MethodsPROTECT, a double-blind, randomised, active-controlled, phase 3 study, was done across 134 clinical practice sites in 18 countries throughout the Americas, Asia, and Europe. Patients aged 18 years or older with biopsy-proven primary IgA nephropathy and proteinuria of at least 1·0 g per day despite maximised renin–angiotensin system inhibition for at least 12 weeks were randomly assigned (1:1) to receive sparsentan (target dose 400 mg oral sparsentan once daily) or irbesartan (target dose 300 mg oral irbesartan once daily) based on a permuted-block randomisation method. The primary endpoint was proteinuria change between treatment groups at 36 weeks. Secondary endpoints included rate of change (slope) of the estimated glomerular filtration rate (eGFR), changes in proteinuria, a composite of kidney failure (confirmed 40% eGFR reduction, end-stage kidney disease, or all-cause mortality), and safety and tolerability up to 110 weeks from randomisation. Secondary efficacy outcomes were assessed in the full analysis set and safety was assessed in the safety set, both of which were defined as all patients who were randomly assigned and received at least one dose of randomly assigned study drug. This trial is registered with ClinicalTrials.gov, NCT03762850.FindingsBetween Dec 20, 2018, and May 26, 2021, 203 patients were randomly assigned to the sparsentan group and 203 to the irbesartan group. One patient from each group did not receive the study drug and was excluded from the efficacy and safety analyses (282 [70%] of 404 included patients were male and 272 [67%] were White) . Patients in the sparsentan group had a slower rate of eGFR decline than those in the irbesartan group. eGFR chronic 2-year slope (weeks 6–110) was −2·7 mL/min per 1·73 m2 per year versus −3·8 mL/min per 1·73 m2 per year (difference 1·1 mL/min per 1·73 m2 per year, 95% CI 0·1 to 2·1; p=0·037); total 2-year slope (day 1–week 110) was −2·9 mL/min per 1·73 m2 per year versus −3·9 mL/min per 1·73 m2 per year (difference 1·0 mL/min per 1·73 m2 per year, 95% CI −0·03 to 1·94; p=0·058). The significant reduction in proteinuria at 36 weeks with sparsentan was maintained throughout the study period; at 110 weeks, proteinuria, as determined by the change from baseline in urine protein-to-creatinine ratio, was 40% lower in the sparsentan group than in the irbesartan group (−42·8%, 95% CI −49·8 to −35·0, with sparsentan versus −4·4%, −15·8 to 8·7, with irbesartan; geometric least-squares mean ratio 0·60, 95% CI 0·50 to 0·72). The composite kidney failure endpoint was reached by 18 (9%) of 202 patients in the sparsentan group versus 26 (13%) of 202 patients in the irbesartan group (relative risk 0·7, 95% CI 0·4 to 1·2). Treatment-emergent adverse events were well balanced between sparsentan and irbesartan, with no new safety signals.InterpretationOver 110 weeks, treatment with sparsentan versus maximally titrated irbesartan in patients with IgA nephropathy resulted in significant reductions in proteinuria and preservation of kidney function

Sparsentan in patients with IgA nephropathy: a prespecified interim analysis from a randomised, double-blind, active-controlled clinical trial

Background: Sparsentan is a novel, non-immunosuppressive, single-molecule, dual endothelin and angiotensin receptor antagonist being examined in an ongoing phase 3 trial in adults with IgA nephropathy. We report the prespecified interim analysis of the primary proteinuria efficacy endpoint, and safety. Methods: PROTECT is an international, randomised, double-blind, active-controlled study, being conducted in 134 clinical practice sites in 18 countries. The study examines sparsentan versus irbesartan in adults (aged ≥18 years) with biopsy-proven IgA nephropathy and proteinuria of 1·0 g/day or higher despite maximised renin-angiotensin system inhibitor treatment for at least 12 weeks. Participants were randomly assigned in a 1:1 ratio to receive sparsentan 400 mg once daily or irbesartan 300 mg once daily, stratified by estimated glomerular filtration rate at screening (30 to 1·75 g/day). The primary efficacy endpoint was change from baseline to week 36 in urine protein-creatinine ratio based on a 24-h urine sample, assessed using mixed model repeated measures. Treatment-emergent adverse events (TEAEs) were safety endpoints. All endpoints were examined in all participants who received at least one dose of randomised treatment. The study is ongoing and is registered with ClinicalTrials.gov, NCT03762850. Findings: Between Dec 20, 2018, and May 26, 2021, 404 participants were randomly assigned to sparsentan (n=202) or irbesartan (n=202) and received treatment. At week 36, the geometric least squares mean percent change from baseline in urine protein-creatinine ratio was statistically significantly greater in the sparsentan group (-49·8%) than the irbesartan group (-15·1%), resulting in a between-group relative reduction of 41% (least squares mean ratio=0·59; 95% CI 0·51-0·69; p<0·0001). TEAEs with sparsentan were similar to irbesartan. There were no cases of severe oedema, heart failure, hepatotoxicity, or oedema-related discontinuations. Bodyweight changes from baseline were not different between the sparsentan and irbesartan groups. Interpretation: Once-daily treatment with sparsentan produced meaningful reduction in proteinuria compared with irbesartan in adults with IgA nephropathy. Safety of sparsentan was similar to irbesartan. Future analyses after completion of the 2-year double-blind period will show whether these beneficial effects translate into a long-term nephroprotective potential of sparsentan. Funding: Travere Therapeutics

Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2-year results from a randomised, active-controlled, phase 3 trial

Background Sparsentan, a novel, non-immunosuppressive, single-molecule, dual endothelin angiotensin receptor antagonist, significantly reduced proteinuria versus irbesartan, an angiotensin II receptor blocker, at 36 weeks (primary endpoint) in patients with immunoglobulin A nephropathy in the phase 3 PROTECT trial's previously reported interim analysis. Here, we report kidney function and outcomes over 110 weeks from the double-blind final analysis. Methods PROTECT, a double-blind, randomised, active-controlled, phase 3 study, was done across 134 clinical practice sites in 18 countries throughout the Americas, Asia, and Europe. Patients aged 18 years or older with biopsy-proven primary IgA nephropathy and proteinuria of at least 1·0 g per day despite maximised renin–angiotensin system inhibition for at least 12 weeks were randomly assigned (1:1) to receive sparsentan (target dose 400 mg oral sparsentan once daily) or irbesartan (target dose 300 mg oral irbesartan once daily) based on a permuted-block randomisation method. The primary endpoint was proteinuria change between treatment groups at 36 weeks. Secondary endpoints included rate of change (slope) of the estimated glomerular filtration rate (eGFR), changes in proteinuria, a composite of kidney failure (confirmed 40% eGFR reduction, end-stage kidney disease, or all-cause mortality), and safety and tolerability up to 110 weeks from randomisation. Secondary efficacy outcomes were assessed in the full analysis set and safety was assessed in the safety set, both of which were defined as all patients who were randomly assigned and received at least one dose of randomly assigned study drug. This trial is registered with ClinicalTrials.gov, NCT03762850. Findings Between Dec 20, 2018, and May 26, 2021, 203 patients were randomly assigned to the sparsentan group and 203 to the irbesartan group. One patient from each group did not receive the study drug and was excluded from the efficacy and safety analyses (282 [70%] of 404 included patients were male and 272 [67%] were White) . Patients in the sparsentan group had a slower rate of eGFR decline than those in the irbesartan group. eGFR chronic 2-year slope (weeks 6–110) was −2·7 mL/min per 1·73 m2 per year versus −3·8 mL/min per 1·73 m2 per year (difference 1·1 mL/min per 1·73 m2 per year, 95% CI 0·1 to 2·1; p=0·037); total 2-year slope (day 1–week 110) was −2·9 mL/min per 1·73 m2 per year versus −3·9 mL/min per 1·73 m2 per year (difference 1·0 mL/min per 1·73 m2 per year, 95% CI −0·03 to 1·94; p=0·058). The significant reduction in proteinuria at 36 weeks with sparsentan was maintained throughout the study period; at 110 weeks, proteinuria, as determined by the change from baseline in urine protein-to-creatinine ratio, was 40% lower in the sparsentan group than in the irbesartan group (−42·8%, 95% CI −49·8 to −35·0, with sparsentan versus −4·4%, −15·8 to 8·7, with irbesartan; geometric least-squares mean ratio 0·60, 95% CI 0·50 to 0·72). The composite kidney failure endpoint was reached by 18 (9%) of 202 patients in the sparsentan group versus 26 (13%) of 202 patients in the irbesartan group (relative risk 0·7, 95% CI 0·4 to 1·2). Treatment-emergent adverse events were well balanced between sparsentan and irbesartan, with no new safety signals. Interpretation Over 110 weeks, treatment with sparsentan versus maximally titrated irbesartan in patients with IgA nephropathy resulted in significant reductions in proteinuria and preservation of kidney function.</p