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Hepatotoxicity associated with intravenous/intrathecal adeno-associated virus (AAV) gene therapy has been observed in preclinical species and patients. In nonhuman primates, hepatotoxicity following self-complementary AAV9 administration varies from asymptomatic transaminase elevation with minimal to mild microscopic changes to symptomatic elevations of liver function and thromboinflammatory markers with microscopic changes consistent with marked hepatocellular necrosis and deteriorating clinical condition. These transient acute liver injury marker elevations occur from 3-4 days post intravenous administration to â¼2 weeks post intrathecal administration. No transaminase elevation or microscopic changes were observed with intrathecal administration of empty capsids or a "promoterless genome" vector, suggesting that liver injury after cerebrospinal fluid dosing in nonhuman primates is driven by viral transduction and transgene expression. Co-administration of prednisolone after intravenous or intrathecal dosing did not prevent liver enzyme or microscopic changes despite a reduction of T lymphocyte infiltration in liver tissue. Similarly, co-administration of rituximab/everolimus with intrathecal dosing failed to block AAV-driven hepatotoxicity. Self-complementary AAV-induced acute liver injury appears to correlate with high hepatocellular vector load, macrophage activation, and type 1 interferon innate virus-sensing pathway responses. The current work characterizes key aspects pertaining to early AAV-driven hepatotoxicity in cynomolgus macaques, highlighting the usefulness of this nonclinical species in that context.
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Enfermedad Hepática Inducida por Sustancias y Drogas , Terapia Genética , Animales , Humanos , Macaca fascicularis/genética , Administración Intravenosa , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/terapia , Dependovirus/genética , Dependovirus/metabolismo , Vectores Genéticos/genéticaRESUMEN
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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Enfermedades Cardiovasculares , Terapia Genética , Animales , Humanos , Ratones , Terapia Genética/efectos adversosRESUMEN
BACKGROUND & AIMS: Spinal muscular atrophy (SMA) is an autosomal recessive, childhood-onset motor neuron disease. Onasemnogene abeparvovec (OA) is a gene therapy designed to address SMA's root cause. In pivotal mouse toxicology studies, the liver was identified as a major site of OA toxicity. Clinical data reflect elevations in serum aminotransferase concentrations, with some reports of serious acute liver injury. Prophylactic prednisolone mitigates these effects. Herein, we aim to provide pragmatic, supportive guidance for identification, management, and risk mitigation of potential drug-induced liver injury. METHODS: Data from 325 patients with SMA who had received OA through 31 December 2019, in 5 clinical trials, a managed access program (MAP), and a long-term registry (RESTORE), and through commercial use, were analyzed. Liver-related adverse events, laboratory data, concomitant medications, and prednisolone use were analyzed. RESULTS: Based on adverse events and laboratory data, 90 of 100 patients had elevated liver function test results (alanine aminotransferase, and/or aspartate aminotransferase, and/or bilirubin concentrations). Of these, liver-associated adverse events were reported for 34 of 100 (34%) and 10 of 43 (23%) patients in clinical trials and MAP/RESTORE, respectively. Two patients in MAP had serious acute liver injury, which resolved completely. While all events in the overall population resolved, prednisolone treatment duration varied (range: 33-229 days), with a majority receiving prednisolone for 60-120 days. More than 60% had elevations in either alanine aminotransferase, aspartate aminotransferase, or bilirubin concentrations prior to dosing. Greater than 40% received potentially hepatotoxic concomitant medications. CONCLUSIONS: Hepatotoxicity is a known risk associated with OA use. Practitioners should identify contributing factors and mitigate risk through appropriate monitoring and intervention. LAY SUMMARY: Onasemnogene abeparvovec is a type of medicine called a "gene therapy," which is used to treat babies and young children who have a rare, serious inherited condition called "spinal muscular atrophy" (SMA). It works by supplying a fully functioning copy of the survival motor neuron or SMN gene, which then helps the body produce enough SMN protein. However, it can cause an immune response that could lead to an increase in enzymes produced by the liver. This article provides information about the liver injury and how to prevent and recognize if it happens, so that it may be treated properly.
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Productos Biológicos/administración & dosificación , Productos Biológicos/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Terapia Genética/métodos , Atrofia Muscular Espinal/terapia , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/efectos adversos , Sistema de Registros , Alanina Transaminasa/sangre , Aspartato Aminotransferasas/sangre , Bilirrubina/sangre , Estudios de Cohortes , Femenino , Glucocorticoides/uso terapéutico , Humanos , Lactante , Recién Nacido , Masculino , Atrofia Muscular Espinal/sangre , Atrofia Muscular Espinal/tratamiento farmacológico , Prednisolona/uso terapéutico , Resultado del TratamientoRESUMEN
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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Productos Biológicos/efectos adversos , Atrofia Muscular Espinal/tratamiento farmacológico , Proteínas Recombinantes de Fusión/efectos adversos , Microangiopatías Trombóticas/inducido químicamente , Productos Biológicos/uso terapéutico , Femenino , Humanos , Lactante , Proteínas Recombinantes de Fusión/uso terapéuticoRESUMEN
Intradialytic hypotension (IDH) is a common adverse event resulting in premature interruption of hemodialysis, and consequently, inadequate fluid and solute removal. IDH occurs in response to the reduction in blood volume during ultrafiltration and subsequent poor compensatory mechanisms due to abnormal cardiac function or autonomic or baroreceptor failure. Pediatric patients are inherently at risk for IDH due to the added difficulty of determining and attaining an accurate dry weight. While frequent blood pressure monitoring, dialysate sodium profiling, ultrafiltration-guided blood volume monitoring, dialysate cooling, hemodiafiltration, and intradialytic mannitol and midodrine have been used to prevent IDH, they have not been extensively studied in pediatric population. Lack of large-scale studies on IDH in children makes it difficult to develop evidence-based management guidelines. Here, we aim to review IDH preventative strategies in the pediatric population and outlay recommendations from the Pediatric Continuous Renal Replacement Therapy (PCRRT) Workgroup. Without strong evidence in the literature, our recommendations from the expert panel reflect expert opinion and serve as a valuable guide.
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Consenso , Terapia de Reemplazo Renal Continuo/normas , Hipotensión/prevención & control , Fallo Renal Crónico/terapia , Factores de Edad , Presión Sanguínea/efectos de los fármacos , Determinación de la Presión Sanguínea , Niño , Terapia de Reemplazo Renal Continuo/efectos adversos , Terapia de Reemplazo Renal Continuo/métodos , Hemodiafiltración/efectos adversos , Hemodiafiltración/métodos , Soluciones para Hemodiálisis/efectos adversos , Humanos , Hipotensión/diagnóstico , Hipotensión/etiología , Midodrina/administración & dosificación , Diálisis Renal/efectos adversos , Diálisis Renal/normas , TemperaturaRESUMEN
BACKGROUND: Intentional or unintentional ingestions among children and adolescents are common. There are a number of ingestions amenable to renal replacement therapy (RRT). METHODS: We systematically searched PubMed/Medline, Embase, and Cochrane databases for literature regarding drugs/intoxicants and treatment with RRT in pediatric populations. Two experts from the PCRRT (Pediatric Continuous Renal Replacement Therapy) workgroup assessed titles, abstracts, and full-text articles for extraction of data. The data from the literature search was shared with the PCRRT workgroup and two expert toxicologists, and expert panel recommendations were developed. RESULTS AND CONCLUSIONS: We have presented the recommendations concerning the use of RRTs for treatment of intoxications with toxic alcohols, lithium, vancomycin, theophylline, barbiturates, metformin, carbamazepine, methotrexate, phenytoin, acetaminophen, salicylates, valproic acid, and aminoglycosides.
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Lesión Renal Aguda/terapia , Consenso , Intoxicación/terapia , Guías de Práctica Clínica como Asunto , Terapia de Reemplazo Renal/normas , Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/etiología , Adolescente , Niño , Preescolar , Conferencias de Consenso como Asunto , Femenino , Humanos , Lactante , Masculino , Nefrología/normas , Intoxicación/diagnóstico , Intoxicación/etiología , Adulto JovenRESUMEN
Hemodialysis (HD) in neonates and infants poses unique challenges due to high risks of mortality attributable to obligatory small blood flow volumes. Although HD is often necessary in neonates, its effectiveness and feasibility are poorly understood. The aim of this review is to describe in detail the few studies reporting on HD in neonates and infants (<12 months old) and then dissertate more broadly on the subject with an emphasis on recent innovations with potential to overcome traditional barriers for effective HD in this population. We detail the clinical characteristics, outcomes, technical considerations, maintenance and complications associated with HD, and provide guidance for addressing challenges associated with HD in this population.
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Lesión Renal Aguda/terapia , Unidades de Cuidado Intensivo Neonatal , Diálisis Renal/métodos , Insuficiencia Renal Crónica/terapia , Lesión Renal Aguda/diagnóstico , Factores de Edad , Toma de Decisiones Clínicas , Femenino , Humanos , Recién Nacido , Masculino , Pronóstico , Diálisis Renal/efectos adversos , Insuficiencia Renal Crónica/diagnóstico , Medición de Riesgo , Resultado del TratamientoRESUMEN
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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Actitud del Personal de Salud , Fallo Renal Crónico/terapia , Nefrología , Pediatría , Adolescente , Niño , Árboles de Decisión , Accesibilidad a los Servicios de Salud , Humanos , Enfermería en Nefrología , Grupo de Atención al Paciente , Calidad de VidaRESUMEN
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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Predisposición Genética a la Enfermedad , Inmunosupresores/efectos adversos , Trasplante de Riñón , Leucopenia/inducido químicamente , Ácido Micofenólico/efectos adversos , Polimorfismo de Nucleótido Simple , Complicaciones Posoperatorias/inducido químicamente , Adolescente , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Estudios de Asociación Genética , Marcadores Genéticos , Humanos , Incidencia , Lactante , Leucopenia/epidemiología , Leucopenia/genética , Modelos Logísticos , Masculino , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/genética , Estudios Retrospectivos , Adulto JovenRESUMEN
Steroid-sensitive nephrotic syndrome (SSNS) accounts for >80% of cases of nephrotic syndrome in childhood. However, the etiology and pathogenesis of SSNS remain obscure. Hypothesizing that coding variation may underlie SSNS risk, we conducted an exome array association study of SSNS. We enrolled a discovery set of 363 persons (214 South Asian children with SSNS and 149 controls) and genotyped them using the Illumina HumanExome Beadchip. Four common single nucleotide polymorphisms (SNPs) in HLA-DQA1 and HLA-DQB1 (rs1129740, rs9273349, rs1071630, and rs1140343) were significantly associated with SSNS at or near the Bonferroni-adjusted P value for the number of single variants that were tested (odds ratio, 2.11; 95% confidence interval, 1.56 to 2.86; P=1.68×10(-6) (Fisher exact test). Two of these SNPs-the missense variants C34Y (rs1129740) and F41S (rs1071630) in HLA-DQA1-were replicated in an independent cohort of children of white European ancestry with SSNS (100 cases and ≤589 controls; P=1.42×10(-17)). In the rare variant gene set-based analysis, the best signal was found in PLCG2 (P=7.825×10(-5)). In conclusion, this exome array study identified HLA-DQA1 and PLCG2 missense coding variants as candidate loci for SSNS. The finding of a MHC class II locus underlying SSNS risk suggests a major role for immune response in the pathogenesis of SSNS.
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Predisposición Genética a la Enfermedad/epidemiología , Cadenas alfa de HLA-DQ/genética , Síndrome Nefrótico/epidemiología , Síndrome Nefrótico/genética , Fosfolipasa C gamma/genética , Esteroides/uso terapéutico , Distribución por Edad , Edad de Inicio , Alelos , Estudios de Casos y Controles , Niño , Preescolar , Estudios de Cohortes , Femenino , Genotipo , Humanos , Incidencia , Masculino , Mutación Missense , Síndrome Nefrótico/tratamiento farmacológico , Distribución por Sexo , Sri Lanka/epidemiologíaRESUMEN
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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Evaluación del Resultado de la Atención al Paciente , Calidad de Vida , Insuficiencia Renal Crónica/complicaciones , Encuestas y Cuestionarios , Adolescente , Niño , Estudios Transversales , Femenino , Humanos , Masculino , Nefrología/métodos , Insuficiencia Renal Crónica/psicología , Autoinforme , Índice de Severidad de la EnfermedadRESUMEN
AIM: The incidence of cardiovascular disease (CVD) in children with chronic kidney disease (CKD) is high. Exposure to second hand smoke (SHS) is a known risk factor for CVD. Due to a recent report of high incidence of SHS in children with CKD, we sought to investigate via questionnaire the smoking behaviors of caregivers of children with CKD. MATERIAL AND METHODS: A cross sectional study was conducted in which caregivers of children and adolescents with CKD were asked to complete a single anonymous self-administered survey. RESULTS: Almost 40% of children and adolescents lived with one or more smokers. Over half of smokers smoked in the presence of their children and in the car. Smokers were significantly less aware of the detrimental effect of SHS exposure on the renal health of their children. Among smokers, almost 70% reported they had not been advised by their child's nephrologist to quit tobacco use. CONCLUSION: There is a high prevalence of SHS exposure among children and adolescents with CKD, which may contribute to CVD. Caregivers are not fully aware of the detrimental effects of SHS exposure on the renal health of their children.
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Enfermedades Cardiovasculares/etiología , Padres/psicología , Insuficiencia Renal Crónica/complicaciones , Contaminación por Humo de Tabaco/efectos adversos , Adolescente , Niño , Estudios Transversales , Femenino , Humanos , MasculinoRESUMEN
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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Lesión Renal Aguda , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/tratamiento farmacológico , Riñón/metabolismo , Riñón/patología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Biomarcadores/metabolismoRESUMEN
INTRODUCTION: Secukinumab is an anti-interleukin (IL)-17A monoclonal antibody indicated for multiple immunological disorders. Here, we aim to summarize secukinumab safety in clinical trials (CTs) and post-marketing setting (PMS) until 25 June 2022. METHODS: Adverse events (AEs) were summarized with crude reporting rate (RR) per 100 patient-years (PY) in PMS for all reported indications and with exposure-adjusted incident rates (EAIR) per 100 PY in pooled 47 CTs for approved indications. RESULTS: Secukinumab exposure totaled 1,159,260 PY in PMS and 27,765 PY in CTs. AEs were mostly (> 80%) non-serious in PMS. EAIR for serious AEs was 7.0/100 PY. Nasopharyngitis (RR 0.59/100 PY, EAIR 16.08/100 PY) and pneumonia (RR 0.14/100 PY, EAIR 0.17/100 PY) were the most common infection and serious infection, respectively. Candida infections (RR 0.20/100 PY, EAIR 2.16/100 PY) were the most common fungal infections. Inflammatory bowel disease (IBD) was observed in PMS (0.14/100 PY) and CTs (0.26/100 PY). Most (76%) patients with prior IBD did not report IBD flare during CTs. PMS monitoring identified paradoxical skin reactions including dyshidrotic eczema (RR 0.006/100 PY) and pyoderma gangrenosum (RR 0.003/100 PY). CONCLUSION: Secukinumab safety profile with increased patient exposure remained favorable. Paradoxical skin reactions were identified in post-marketing monitoring.
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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 Nefrótico/psicología , Calidad de Vida/psicología , Adolescente , Niño , Estudios Transversales , Femenino , Humanos , Masculino , Medio Oeste de Estados Unidos , Reproducibilidad de los Resultados , Autoinforme , Encuestas y CuestionariosRESUMEN
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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Enfermedades Cardiovasculares/prevención & control , Enfermedades Renales/complicaciones , Calidad de la Atención de Salud , Adolescente , Adulto , Femenino , Humanos , Masculino , Medición de Riesgo , Factores de RiesgoRESUMEN
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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Fallo Renal Crónico , Médicos , Humanos , Niño , Diálisis Renal , Estudios Transversales , Conocimientos, Actitudes y Práctica en Salud , Estudios Prospectivos , Fallo Renal Crónico/terapia , Ejercicio FísicoRESUMEN
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.