RESUMO
Human gene replacement therapies such as onasemnogene abeparvovec (OA) use recombinant adeno-associated virus (rAAV) vectors to treat monogenic disorders. The heart and liver are known target organs of toxicity in animals; with cardiac and hepatic monitoring recommended in humans after OA dosing. This manuscript provides a comprehensive description of cardiac data from preclinical studies and clinical sources including clinical trials, managed access programs and the post-marketing setting following intravenous OA administration through 23 May 2022. Single dose mouse GLP-Toxicology studies revealed dose-dependent cardiac findings including thrombi, myocardial inflammation and degeneration/regeneration, which were associated with early mortality (4-7 weeks) in the high dose groups. No such findings were documented in non-human primates (NHP) after 6 weeks or 6 months post-dose. No electrocardiogram or echocardiogram abnormalities were noted in NHP or humans. After OA dosing, some patients developed isolated elevations in troponin without associated signs/symptoms; the reported cardiac adverse events in patients were considered of secondary etiology (e.g. respiratory dysfunction or sepsis leading to cardiac events). Clinical data indicate cardiac toxicity observed in mice does not translate to humans. Cardiac abnormalities have been associated with SMA. Healthcare professionals should use medical judgment when evaluating the etiology and assessment of cardiac events post OA dosing so as to consider all possibilities and manage the patient accordingly.
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Doenças Cardiovasculares , Terapia Genética , Animais , Humanos , Camundongos , Terapia Genética/efeitos adversosRESUMO
Spinal muscular atrophy is treated with onasemnogene abeparvovec, which replaces the missing survival motor neuron 1 gene via an adeno-associated virus vector. As of July 1, 2020, we had identified 3 infants who developed thrombotic microangiopathy following onasemnogene abeparvovec. Early recognition and treatment of drug-induced thrombotic microangiopathy may lessen mortality and morbidity.
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Produtos Biológicos/efeitos adversos , Atrofia Muscular Espinal/tratamento farmacológico , Proteínas Recombinantes de Fusão/efeitos adversos , Microangiopatias Trombóticas/induzido quimicamente , Produtos Biológicos/uso terapêutico , Feminino , Humanos , Lactente , Proteínas Recombinantes de Fusão/uso terapêuticoRESUMO
The care of children with end-stage renal disease (ESRD) is highly specialized and often poorly understood by nonpediatric providers and facility/institution administrators. As such, this position paper has been created to offer provider, facility, and institutional guidance regarding the components of care necessary for children receiving dialysis. Key differences between adult and pediatric dialysis units are highlighted. Responsibilities and expectations of the members of the interdisciplinary dialysis team are outlined as they pertain specifically to the care of pediatric dialysis patients. Physical and staffing requirements of the dialysis facility are reviewed, again focusing on unique needs and challenges faced by the pediatric dialysis care team. Among these, vascular access options and proper planning of ESRD care are underscored. Pediatric quality-of-life metrics differ significantly from adult quality variables, and proper tools for assessment must be used. Endorsed by the Council of the American Society of Pediatric Nephrology (ASPN), this position paper serves as a reference tool for the provision of care to pediatric patients with ESRD.
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Atitude do Pessoal de Saúde , Falência Renal Crônica/terapia , Nefrologia , Pediatria , Adolescente , Criança , Árvores de Decisões , Acessibilidade aos Serviços de Saúde , Humanos , Enfermagem em Nefrologia , Equipe de Assistência ao Paciente , Qualidade de VidaRESUMO
MMF is commonly prescribed following kidney transplantation, yet its use is complicated by leukopenia. Understanding the genetics mediating this risk will help clinicians administer MMF safely. We evaluated 284 patients under 21 years of age for incidence and time course of MMF-related leukopenia and performed a candidate gene association study comparing the frequency of 26 SNPs between cases with MMF-related leukopenia and controls. We matched cases by induction, steroid duration, race, center, and age. We also evaluated the impact of induction and SNPs on time to leukopenia in all cases. Sixty-eight (24%) patients had MMF-related leukopenia, of which 59 consented for genotyping and 38 were matched with controls. Among matched pairs, no SNPs were associated with leukopenia. With non-depleting induction, UGT2B7-900A>G (rs7438135) was associated with increased risk of MMF-related leukopenia (P = .038). Time to leukopenia did not differ between patients by induction agent, but 2 SNPs (rs2228075, rs2278294) in IMPDH1 were associated with increased time to leukopenia. MMF-related leukopenia is common after transplantation. UGT2B7 may influence leukopenia risk especially in patients without lymphocyte-depleting induction. IMPDH1 may influence time course of leukopenia after transplant.
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Predisposição Genética para Doença , Imunossupressores/efeitos adversos , Transplante de Rim , Leucopenia/induzido quimicamente , Ácido Micofenólico/efeitos adversos , Polimorfismo de Nucleotídeo Único , Complicações Pós-Operatórias/induzido quimicamente , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Estudos de Associação Genética , Marcadores Genéticos , Humanos , Incidência , Lactente , Leucopenia/epidemiologia , Leucopenia/genética , Modelos Logísticos , Masculino , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/genética , Estudos Retrospectivos , Adulto JovemRESUMO
BACKGROUND AND OBJECTIVES: Chronic kidney disease is a persistent chronic health condition commonly seen in pediatric nephrology programs. Our study aims to evaluate the sensitivity of the Patient Reported Outcomes Measurement Information System (PROMIS) pediatric instrument to indicators of disease severity and activity in pediatric chronic kidney disease. METHODS: This cross sectional study included 233 children 8-17 years old, with chronic kidney disease from 16 participating institutions in North America. Disease activity indicators, including hospitalization in the previous 6 months, edema, and number of medications consumed daily, as well as disease severity indicators of kidney function and coexisting medical conditions were captured. PROMIS domains, including depression, anxiety, social-peer relationships, pain interference, fatigue, mobility, and upper extremity function, were administered via web-based questionnaires. Absolute effect sizes (AES) were generated to demonstrate the impact of disease on domain scores. Four children were excluded because of missing glomerular filtration rate (GFR) estimations. RESULTS: Of the 229 children included in the final analysis, 221 completed the entire PROMIS questionnaire. Unadjusted PROMIS domains were responsive to chronic kidney disease activity indicators and number of coexisting conditions. PROMIS domain scores were worse in the presence of recent hospitalizations (depression AES 0.33, anxiety AES 0.42, pain interference AES 0.46, fatigue AES 0.50, mobility AES 0.49), edema (depression AES 0.50, anxiety AES 0.60, pain interference AES 0.77, mobility AES 0.54) and coexisting medical conditions (social peer-relationships AES 0.66, fatigue AES 0.83, mobility AES 0.60, upper extremity function AES 0.48). CONCLUSIONS: The PROMIS pediatric domains of depression, anxiety, social-peer relationships, pain interference, and mobility were sensitive to the clinical status of children with chronic kidney disease in this multi-center cross sectional study. We demonstrated that a number of important clinical characteristics including recent history of hospitalization and edema, affected patient perceptions of depression, anxiety, pain interference, fatigue and mobility. The PROMIS instruments provide a potentially valuable tool to study the impact of chronic kidney disease. Additional studies will be required to assess responsiveness in PROMIS score with changes in disease status over time.
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Avaliação de Resultados da Assistência ao Paciente , Qualidade de Vida , Insuficiência Renal Crônica/complicações , Inquéritos e Questionários , Adolescente , Criança , Estudos Transversais , Feminino , Humanos , Masculino , Nefrologia/métodos , Insuficiência Renal Crônica/psicologia , Autorrelato , Índice de Gravidade de DoençaRESUMO
The kidneys play a pivotal role in elimination of most drugs; therefore, a comprehensive understanding of renal physiology and pathology is important for those involved in drug development. High filtration capacity and metabolic activity make the kidneys vulnerable to drug-induced nephrotoxicity (DIN). Acute DIN may manifest on a background of renal impairment that has resulted from underlying disease, previously administered nephrotoxic medications, congenital renal abnormalities, or the natural aging process. The ability of the kidneys to compensate for DIN depends on the degree of pre-insult renal function. Therefore, it can be difficult to identify. The discovery and development of novel biomarkers that can diagnose kidney damage earlier and more accurately than current clinical measures and may be effective in detecting DIN. The goal of this manuscript is to provide a pragmatic and evidence-based supportive guidance for the early identification and management of DIN during the drug development process for clinical trial participants of all ages. The overall objective is to minimize the impact of DIN on kidney function and to collect renal safety data enabling risk analysis and mitigation.
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Injúria Renal Aguda , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/tratamento farmacológico , Rim/metabolismo , Rim/patologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Biomarcadores/metabolismoRESUMO
BACKGROUND AND OBJECTIVES: Nephrotic syndrome (NS) represents a common disease in pediatric nephrology typified by a relapsing and remitting course and characterized by the presence of edema that can significantly affect the health-related quality of life in children and adolescents. The PROMIS pediatric measures were constructed to be publically available, efficient, precise, and valid across a variety of diseases to assess patient reports of symptoms and quality of life. This study was designed to evaluate the ability of children and adolescents with NS to complete the PROMIS assessment via computer and to initiate validity assessments of the short forms and full item banks in pediatric NS. Successful measurement of patient reported outcomes will contribute to our understanding of the impact of NS on children and adolescents. DESIGN: This cross-sectional study included 151 children and adolescents 8-17 years old with NS from 16 participating institutions in North America. The children completed the PROMIS pediatric depression, anxiety, social-peer relationships, pain interference, fatigue, mobility and upper extremity functioning measures using a web-based interface. Responses were compared between patients experiencing active NS (n = 53) defined by the presence of edema and patients with inactive NS (n = 96) defined by the absence of edema. RESULTS: All 151 children and adolescents were successfully able to complete the PROMIS assessment via computer. As hypothesized, the children and adolescents with active NS were significantly different on 4 self-reported measures (anxiety, pain interference, fatigue, and mobility). Depression, peer relationships, and upper extremity functioning were not different between children with active vs. inactive NS. Multivariate analysis showed that the PROMIS instruments remained sensitive to NS disease activity after adjusting for demographic characteristics. CONCLUSIONS: Children and adolescents with NS were able to successfully complete the PROMIS instrument using a web-based interface. The computer based pediatric PROMIS measurement effectively discriminated between children and adolescents with active and inactive NS. The domain scores found in this study are consistent with previous reports investigating the health-related quality of life in children and adolescents with NS. This study establishes known-group validity and feasibility for PROMIS pediatric measures in children and adolescents with NS.
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Síndrome Nefrótica/psicologia , Qualidade de Vida/psicologia , Adolescente , Criança , Estudos Transversais , Feminino , Humanos , Masculino , Meio-Oeste dos Estados Unidos , Reprodutibilidade dos Testes , Autorrelato , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Cardiovascular disease is the leading cause of increased mortality for adolescents with advanced kidney disease. The quality of preventive cardiovascular care may impact long-term outcomes for these patients. METHODS: We reviewed the records of 196 consecutive adolescents from eight centers with pre-dialysis chronic kidney disease, on dialysis or with a kidney transplant, who transferred to adult-focused providers. We compared cardiovascular risk assessment and therapy within and across centers. Predictors of care were assessed using multilevel models. RESULTS: Overall, 58 % (range 44-86 %; p = 0.08 for variance) of five recommended cardiovascular risk assessments were documented. Recommended therapy for six modifiable cardiovascular risk factors was documented 57 % (26-76 %; p = 0.09) of the time. Of these patients, 30 % (n = 59) were reported to go through formal transition which was independently associated with a 21 % increase in composite cardiovascular risk assessment (p < 0.001). Transfer after 2006 and kidney transplant status were also associated with increased cardiovascular risk assessment (p < 0.01 and p = 0.045, respectively). CONCLUSIONS: Adolescents with kidney disease receive suboptimal preventive cardiovascular care, that may contribute to their high risk of future cardiovascular mortality. A great opportunity exists to improve outcomes for children with kidney disease by improving the reliability of preventive care that may include formal transition programs.
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Doenças Cardiovasculares/prevenção & controle , Nefropatias/complicações , Qualidade da Assistência à Saúde , Adolescente , Adulto , Feminino , Humanos , Masculino , Medição de Risco , Fatores de RiscoRESUMO
INTRODUCTION: Epidemiologic studies of physical activity among pediatric hemodialysis (HD) patients are lacking. A sedentary lifestyle in End-Stage Kidney Disease is associated with a higher cardiovascular mortality risk. In those patients receiving HD, time spent on dialysis and restrictions on physical activity due to access also contribute. No consensus exists regarding physical activity restrictions based on vascular access type. The aim of this study was to describe the patterns of physical activity restrictions imposed by pediatric nephrologists on pediatric HD patients and to understand the basis for these restrictions. METHODS: We conducted a cross-sectional study involving US pediatric nephrologists using an anonymized survey through Pediatric Nephrology Research Consortium. The survey consisted of 19 items, 6 questions detailed physician characteristics with the subsequent 13 addressing physical activity restrictions. FINDINGS: A total of 35 responses (35% response rate) were received. The average years in practice after fellowship was 11.5 years. Significant restrictions were placed on physical activity and water exposure. None of the participants reported accesses damage or loss that was attributed to physical activity and sport participation. Physicians practice is based on their personal experience, standard practice at their HD center, and clinical practices they were taught. DISCUSSION: There is no consensus among pediatric nephrologists about allowable physical activity in children receiving HD. Due to the lack of objective data, individual physician beliefs have been utilized to restrict activities in the absence of any deleterious effects to accesses. This survey clearly demonstrates the need for more prospective and detailed studies to develop guidelines regarding physical activity and dialysis access in order to optimize quality of care in these children.
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Falência Renal Crônica , Médicos , Humanos , Criança , Diálise Renal , Estudos Transversais , Conhecimentos, Atitudes e Prática em Saúde , Estudos Prospectivos , Falência Renal Crônica/terapia , Exercício FísicoRESUMO
In nonhuman primates (NHPs), adeno-associated virus serotype 9 (AAV9) vectorized gene therapy can cause asymptomatic microscopic injury to dorsal root ganglia (DRG) and trigeminal ganglia (TG) somatosensory neurons, causing neurofilament light chain (NfL) to diffuse into cerebrospinal fluid (CSF) and blood. Data from 260 cynomolgus macaques administered vehicle or AAV9 vectors (intrathecally or intravenously) were analyzed to investigate NfL as a soluble biomarker for monitoring DRG/TG microscopic findings. The incidence of key DRG/TG findings with AAV9 vectors was 78% (maximum histopathology severity, moderate) at 2-12 weeks after the dose. When examined up to 52 weeks after the dose, the incidence was 42% (maximum histopathology severity, minimal). Terminal NfL concentrations in plasma, serum, and CSF correlated with microscopic severity. After 52 weeks, NfL returned to pre-dose baseline concentrations, correlating with microscopic findings of lesser incidence and/or severity compared with interim time points. Blood and CSF NfL concentrations correlated with asymptomatic DRG/TG injury, suggesting that monitoring serum and plasma concentrations is as useful for assessment as more invasive CSF sampling. Longitudinal assessment of NfL concentrations related to microscopic findings associated with AAV9 administration in NHPs indicates NfL could be a useful biomarker in nonclinical toxicity testing. Caution should be applied for any translation to humans.
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BACKGROUND: The National Kidney Foundation Dialysis Outcomes Quality Initiative (NKF-K/DOQI) guidelines recommend the delivered dose of hemodialysis (HD) be measured no less than monthly by checking Kt/V (K is effective urea clearance, t is minute and V is urea distribution). To date, no studies have explored whether the day of the week for checking maintenance HD laboratory studies impacts dialysis dosing. METHODS: Data were collected at two HD facilities on 19 patients, ages ≤ 21 years receiving maintenance HD thrice weekly over a consecutive 6-month period. Data obtained from the Monday and Wednesday of each full third week of the month included dialysis vintage, ultrafiltration volume, serum electrolytes, hemoglobin and clearances. RESULTS: Kt/V and K+ were significantly different between Monday and Wednesday (P = 0.013 and P = 0.047, respectively). CONCLUSION: Due to variability in values based on the day of laboratory evaluations, the dialysis provider must consider the impact of this on the quality of patient care when prescribing dialysis. Research on a larger scale needs to be conducted to allow for better decision-making capabilities in the chronic HD population.
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Creatinina/sangue , Falência Renal Crônica/terapia , Diálise Renal/métodos , Ureia/metabolismo , Adolescente , Fatores Etários , Análise Química do Sangue , Criança , Estudos de Coortes , Soluções para Diálise/administração & dosagem , Feminino , Seguimentos , Unidades Hospitalares de Hemodiálise , Hemoglobinas/análise , Humanos , Falência Renal Crônica/diagnóstico , Testes de Função Renal , Cinética , Masculino , Monitorização Fisiológica/métodos , Potássio/sangue , Estudos Prospectivos , Controle de Qualidade , Diálise Renal/efeitos adversos , Medição de Risco , Resultado do Tratamento , Aumento de PesoRESUMO
BACKGROUND: Spinal muscular atrophy is a rare, neurodegenerative disorder caused by biallelic deletions in the survival motor neuron (SMN1) gene. Onasemnogene abeparvovec is a one-time, intravenous gene replacement therapy designed to deliver the SMN1 transgene. Although available in many geographies, it is not approved globally. The Global Managed Access Program (GMAP) expanded treatment access to patients in countries where treatment was not approved. Previous onasemnogene abeparvovec clinical trials included patients with body weight <8.5 kg. Through GMAP, children weighing ≥8.5 kg received onasemnogene abeparvovec. We describe safety data for heavier patients in GMAP. METHODS: GMAP records were reviewed to identify patients weighing ≥8.5 kg at onasemnogene abeparvovec dosing. To obtain corresponding adverse event (AE) data, the Novartis ARGUS safety database was searched using patient identification numbers and birth dates/dosing dates for any reported AE for GMAP patients. RESULTS: As of September 2, 2021, 102 patients weighing ≥8.5 kg at time of dosing were identified. Fifty-four (53%) had one or more reported AEs. Three patients were reported to be deceased. All three deaths were assessed to be secondary to acute respiratory events. Most (62%) AEs were non-serious. The most frequently reported AEs included increases in hepatic laboratory values, decreased platelets and thrombocytopenia, pyrexia, vomiting, and decreased appetite. CONCLUSIONS: Safety findings for patients weighing ≥8.5 kg administered onasemnogene abeparvovec through GMAP were consistent with those described in clinical trials and included hepatotoxicity, thrombotic microangiopathy, and thrombocytopenia.
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Atrofia Muscular Espinal , Atrofias Musculares Espinais da Infância , Trombocitopenia , Criança , Terapia Genética , Humanos , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/terapia , Atrofias Musculares Espinais da Infância/terapia , Trombocitopenia/etiologiaRESUMO
The main aim of this study was to compare the response to trivalent inactivated influenza vaccine in children who received a kidney transplant and were on steroid-free versus steroid-based immunosuppression. Groups: 1. Kidney transplant recipients on steroid-free immunosuppression (n=27); 2. Kidney transplant recipients on steroid-based immunosuppression (n=39); 3. Healthy controls (n=21). Hemagglutination inhibition titers against 2007-2008 A/H1N1 and A/H3N2 and B strains were measured before and 8 weeks postvaccination. Postvaccination geometric mean titers to A/H1N1 were significantly lower among both transplant groups than controls (p=0.025 and 0.015, respectively). Postvaccination titers to H3N2 and B strains were not statistically different between groups. Proportions of participants developing seroprotection were not different among groups. Both kidney transplant groups seroconverted less than controls for A/H1N1 (p=0.0002) and were no different from controls for B. For A/H3N2, the steroid-free group had the weakest seroconversion (p=0.008), possibly due to mycophenolate-enhanced exposure and a younger age. Overall, children after kidney transplantation demonstrated a good serologic response to the inactivated influenza vaccine although somewhat lower than controls. Steroid-free immunosuppression did not seem to present an advantage in antibody response. Data on inactivated influenza vaccine safety and efficacy was collected and demonstrated absence of acute rejection or laboratory-proven influenza for 6 months postvaccination.
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Imunossupressores/uso terapêutico , Vacinas contra Influenza/administração & dosagem , Influenza Humana/prevenção & controle , Transplante de Rim , Esteroides/uso terapêutico , Doença Aguda , Adolescente , Anticorpos Antivirais/sangue , Canadá , Distribuição de Qui-Quadrado , Criança , Feminino , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Testes de Inibição da Hemaglutinação , Humanos , Esquemas de Imunização , Imunossupressores/efeitos adversos , Vírus da Influenza A Subtipo H1N1/imunologia , Vírus da Influenza A Subtipo H3N2/imunologia , Vacinas contra Influenza/efeitos adversos , Influenza Humana/virologia , Transplante de Rim/efeitos adversos , Masculino , Esteroides/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Estados UnidosRESUMO
INTRODUCTION: This is the first description of safety data for intravenous onasemnogene abeparvovec, the only approved systemically administered gene-replacement therapy for spinal muscular atrophy. OBJECTIVE: We comprehensively assessed the safety of intravenous onasemnogene abeparvovec from preclinical studies, clinical studies, and postmarketing data. METHODS: Single-dose toxicity studies were performed in neonatal mice and juvenile or neonatal cynomolgus nonhuman primates (NHPs). Data presented are from a composite of preclinical studies, seven clinical trials, and postmarketing sources (clinical trials, n = 102 patients; postmarketing surveillance, n = 665 reported adverse event [AE] cases). In clinical trials, safety was assessed through AE monitoring, vital-sign and cardiac assessments, laboratory evaluations, physical examinations, and concomitant medication use. AE reporting and available objective clinical data from postmarketing programs were evaluated. RESULTS: The main target organs of toxicity in mice were the heart and liver. Dorsal root ganglia (DRG) inflammation was observed in NHPs. Patients exhibited no evidence of sensory neuropathy upon clinical examination. In clinical trials, 101/102 patients experienced at least one treatment-emergent AE. In total, 50 patients experienced serious AEs, including 11 considered treatment related. AEs consistent with hepatotoxicity resolved with prednisolone in clinical trials. Transient decreases in mean platelet count were detected but were without bleeding complications. Thrombotic microangiopathy (TMA) was observed in the postmarketing setting. No evidence of intracardiac thrombi was observed for NHPs or patients. CONCLUSIONS: Risks associated with onasemnogene abeparvovec can be anticipated, monitored, and managed. Hepatotoxicity events resolved with prednisolone. Thrombocytopenia was transient. TMA may require medical intervention. Important potential risks include cardiac AEs and DRG toxicity.
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Produtos Biológicos , Terapia Genética , Atrofia Muscular Espinal , Animais , Produtos Biológicos/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Ensaios Clínicos como Assunto , Terapia Genética/efeitos adversos , Humanos , Camundongos , Atrofia Muscular Espinal/tratamento farmacológico , Prednisolona/uso terapêuticoRESUMO
BACKGROUND: Spinal muscular atrophy type 1 is a motor neuron disorder resulting in death or the need for permanent ventilation by age 2 years. We aimed to evaluate the safety and efficacy of onasemnogene abeparvovec (previously known as AVXS-101), a gene therapy delivering the survival motor neuron gene (SMN), in symptomatic patients (identified through clinical examination) with infantile-onset spinal muscular atrophy. METHODS: STR1VE was an open-label, single-arm, single-dose, phase 3 trial done at 12 hospitals and universities in the USA. Eligible patients had to be younger than 6 months and have spinal muscular atrophy with biallelic SMN1 mutations (deletion or point mutations) and one or two copies of SMN2. Patients received a one-time intravenous infusion of onasemnogene abeparvovec (1·1â×â1014 vector genomes per kg) for 30-60 min. During the outpatient follow-up, patients were assessed once per week, beginning at day 7 post-infusion for 4 weeks and then once per month until the end of the study (age 18 months or early termination). Coprimary efficacy outcomes were independent sitting for 30 s or longer (Bayley-III item 26) at the 18 month of age study visit and survival (absence of death or permanent ventilation) at age 14 months. Safety was assessed through evaluation of adverse events, concomitant medication usage, physical examinations, vital sign assessments, cardiac assessments, and laboratory evaluation. Primary efficacy endpoints for the intention-to-treat population were compared with untreated infants aged 6 months or younger (n=23) with spinal muscular atrophy type 1 (biallelic deletion of SMN1 and two copies of SMN2) from the Pediatric Neuromuscular Clinical Research (PNCR) dataset. This trial is registered with ClinicalTrials.gov, NCT03306277 (completed). FINDINGS: From Oct 24, 2017, to Nov 12, 2019, 22 patients with spinal muscular atrophy type 1 were eligible and received onasemnogene abeparvovec. 13 (59%, 97·5% CI 36-100) of 22 patients achieved functional independent sitting for 30 s or longer at the 18 month of age study visit (vs 0 of 23 patients in the untreated PNCR cohort; p<0·0001). 20 patients (91%, 79-100]) survived free from permanent ventilation at age 14 months (vs 6 [26%], 8-44; p<0·0001 in the untreated PNCR cohort). All patients who received onasemnogene abeparvovec had at least one adverse event (most common was pyrexia). The most frequently reported serious adverse events were bronchiolitis, pneumonia, respiratory distress, and respiratory syncytial virus bronchiolitis. Three serious adverse events were related or possibly related to the treatment (two patients had elevated hepatic aminotransferases, and one had hydrocephalus). INTERPRETATION: Results from this multicentre trial build on findings from the phase 1 START study by showing safety and efficacy of commercial grade onasemnogene abeparvovec. Onasemnogene abeparvovec showed statistical superiority and clinically meaningful responses when compared with observations from the PNCR natural history cohort. The favourable benefit-risk profile shown in this study supports the use of onasemnogene abeparvovec for treatment of symptomatic patients with genetic or clinical characteristics predictive of infantile-onset spinal muscular atrophy type 1. FUNDING: Novartis Gene Therapies.
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Produtos Biológicos/uso terapêutico , Terapia Genética/métodos , Proteínas Recombinantes de Fusão/uso terapêutico , Atrofias Musculares Espinais da Infância/tratamento farmacológico , Atrofias Musculares Espinais da Infância/genética , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Proteína 2 de Sobrevivência do Neurônio Motor/genética , Resultado do TratamentoRESUMO
Bacterial peritonitis is a major cause of morbidity in pediatric peritoneal dialysis (PD) patients and can lead to catheter removal, hospitalizations, peritoneal membrane dysfunction, and sepsis. The goal of this prospective study was to determine whether the incidence of peritonitis had improved over time and what practice patterns influenced peritonitis. Two cohorts of PD patients within the End-stage Renal Disease (ESRD) Networks 9/10 and who were <21 years old were prospectively followed for 1 year in 1991 and 2002 and included 70 and 82 patients, respectively. A questionnaire was completed for each patient outlining demographic, clinical, and dialysis characteristics. A second questionnaire was completed for each peritonitis episode. The 2002 cohort was younger, included more nonwhites, and had fewer peritonitis episodes. A shift in practice patterns was evident, with more of the 2002 cohort receiving prophylactic antibiotics and omentectomy at catheter insertion and using cycler machines with a parent operator. Peritonitis-free interval was 10.8 months in 1991 and 17.3 months in 2002. The only variable statistically related to the lower rate of peritonitis in 2002 was fewer prior peritonitis events. The results show an improvement in peritonitis-free interval in studied patients on PD, which appears to be related to numerous changes in practice patterns.
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Infecções Bacterianas/terapia , Falência Renal Crônica/terapia , Diálise Peritoneal/efeitos adversos , Peritonite/terapia , Prática Profissional , Adolescente , Antibioticoprofilaxia , Infecções Bacterianas/etiologia , Infecções Bacterianas/prevenção & controle , Criança , Intervalo Livre de Doença , Feminino , Humanos , Falência Renal Crônica/complicações , Masculino , Diálise Peritoneal Ambulatorial Contínua , Peritonite/microbiologia , Peritonite/prevenção & controle , Estudos Prospectivos , Inquéritos e Questionários , Resultado do Tratamento , Adulto JovemRESUMO
In the current era of dialysis care, the nephrologist must be prepared to perform multiple functions beyond the delivery of patient care. One potential role that the nephrologist may assume is the medical director of a dialysis facility. The medical director is responsible for the unit functions on several levels. This article will aim to review the basic principles involved in the administration of a dialysis unit (DU), including administrative, regulatory, and fiscal aspects. This review is not meant to be comprehensive in nature, but rather is aimed to introduce the trainee and junior faculty to the nuances of the DU.
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Instituições de Assistência Ambulatorial/organização & administração , Diálise Renal , Criança , HumanosRESUMO
INTRODUCTION: This analysis explored laboratory mineral and bone disorder parameters and management of secondary hyperparathyroidism in patients undergoing hemodialysis in Belgium, Canada, China, France, Germany, Italy, Japan, Russia, Saudi Arabia, Spain, Sweden, the UK, and the USA. METHODS: Analyses used demographic, medication, and laboratory data collected in the prospective Dialysis Outcomes and Practice Patterns Study (2012-2015). The analysis included 20,612 patients in 543 facilities. Descriptive data are presented as regional mean (standard deviation), median (interquartile range), or prevalence, weighted for facility sampling fraction. No testing of statistical hypotheses was conducted. RESULTS: The frequency of serum intact parathyroid hormone levels > 600 pg/mL was lowest in Japan (1%) and highest in Russia (30%) and Saudi Arabia (27%). The frequency of serum phosphorus levels > 7.0 mg/dL was lowest in France (4%), the UK (6%), and Spain (6%), and highest in China (27%). The frequency of serum calcium levels > 10.0 mg/dL was highest in the UK (14%) and China (13%) versus 2% to 9% elsewhere. Dialysate calcium concentrations of 2.5 mEq/mL were common in the USA (78%) and Canada (71%); concentrations of 3.0-3.5 mEq/L were almost universal at facilities in Italy, France, and Saudi Arabia (each ≥ 99%). CONCLUSIONS: Wide international variation in mineral and bone disorder laboratory parameters and management practices related to secondary hyperparathyroidism suggests opportunities for optimizing care.
Assuntos
Doenças Ósseas Metabólicas , Procedimentos Clínicos/classificação , Hiperparatireoidismo Secundário , Falência Renal Crônica/terapia , Doenças Ósseas Metabólicas/epidemiologia , Doenças Ósseas Metabólicas/etiologia , Doenças Ósseas Metabólicas/metabolismo , Doenças Ósseas Metabólicas/terapia , Cálcio/sangue , Gerenciamento Clínico , Feminino , Humanos , Hiperparatireoidismo Secundário/sangue , Hiperparatireoidismo Secundário/epidemiologia , Hiperparatireoidismo Secundário/terapia , Internacionalidade , Laboratórios , Masculino , Pessoa de Meia-Idade , Hormônio Paratireóideo/sangue , Prevalência , Estudos Prospectivos , Diálise Renal/efeitos adversos , Diálise Renal/métodosRESUMO
The National Kidney Foundation Dialysis Outcomes Quality Initiative (NKF-DOQI) recommends the use of a permanent vascular access for pediatric hemodialysis (HD) patients; however, central venous catheters are the most common vascular access used among children. In children receiving HD, central venous catheters, while suboptimal, are the most common vascular access used. As such, it is imperative that pediatric HD providers optimize vascular access techniques. We report outcomes of arteriovenous fistula (AVF) creation by a single surgeon in pediatric HD patients dialyzed at a single center. We further describe our experience and outcomes with the use of the operating microscope in the United States in children receiving HD under 15 kg in weight and as young as 4 years of age. AVF usage rates as well as short- and long-term patency rates can be quite high with proper management. We further illustrate that the Fistula First principles can be applied to the pediatric population in the setting of a single surgeon with single center experience. As such, we have surpassed the current NKF-DOQI recommendation of 50% fistula use in prevalent HD patients.